Piperidine cyclic compounds, their synthetic methods, pharmaceutically acceptable salts and applications

Abstract

This invention discloses a piperidine cyclic compound and its synthesis method, pharmaceutically acceptable salts, and applications, belonging to the field of pharmaceutical technology. This piperidine cyclic compound exhibits an enhanced transcriptional effect on CPT1α, a key gene for fatty acid β-oxidation downstream of peroxisome proliferator-activated receptor α (PPARα). This compound is expected to serve as a potential drug for the treatment of non-alcoholic fatty liver disease.

Description

Technical Field

[0001] This invention relates to a piperidine cyclic compound, its synthesis method, pharmaceutically acceptable salts, and applications, belonging to the field of pharmaceutical technology. Background Technology

[0002] Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play a crucial role in the transcriptional regulation of glucose and lipid metabolism. The PPAR family comprises three members: PPARα (NR1C1), PPARδ (NR1C2), and PPARγ, which are expressed in different tissues and perform specific biological functions. Specifically, activation of PPARα primarily regulates fatty acid oxidation (FAO), reducing serum triglyceride levels and maintaining energy homeostasis. Activation of PPARγ enhances the sensitivity of insulin signaling and regulates lipogenesis, while activation of PPARδ enhances fatty acid synthesis. PPARα controls the expression of genes involved in lipoprotein and triglyceride (TG) metabolism, fatty acid oxidation (especially β-oxidation), cellular uptake and export of fatty acids, and indirect lipogenesis. These characteristics, coupled with its involvement in metabolic diseases, make PPARα an ideal target for developing novel therapies for dyslipidemia, metabolic syndrome, diabetes, non-alcoholic fatty liver disease (NAFLD), and their associated cardiovascular complications. Furthermore, experiments and studies have also shown that PPARα has potential therapeutic effects in immune regulation, anti-inflammation, and neurodegenerative diseases. Therefore, it is particularly urgent to develop a drug that can specifically activate PPARα to improve dyslipidemia, and this drug should avoid adverse reactions such as weight gain, edema, or activation of other PPAR subtypes. Summary of the Invention

[0003] This invention provides a piperidine cyclic compound, its synthesis method, pharmaceutically acceptable salts, and applications, aiming to overcome the challenges faced by existing agonists targeting peroxisome proliferator-activated receptor α (PPARα), including the scarcity of drug types, low selectivity, limited agonistic activity, and insufficient bioavailability.

[0004] The technical solution adopted by this invention to solve its technical problem is: In a first aspect, this application provides a piperidine cyclic compound having the structure shown in structural formula I: Structural Formula I Wherein, R is a C1-C10 substituted or unsubstituted alkyl, a C1-C6 substituted or unsubstituted cycloalkyl, a C6-C12 substituted or unsubstituted aryl, or a C4-C6 substituted or unsubstituted heteroaryl; R1 is an optionally substituted methoxyphenyl; R2 is H, a C1-C6 substituted or unsubstituted alkyl, a C1-C6 substituted or unsubstituted cycloalkyl, a C6-C12 substituted or unsubstituted aryl, or a C4-C6 substituted or unsubstituted heteroaryl.

[0005] Secondly, this application provides pharmaceutically acceptable salts of the piperidine cyclic compounds described in the first aspect.

[0006] Thirdly, this application provides a method for synthesizing piperidine cyclic compounds, comprising the following steps: 5-Bromopyridin-3-ol was reacted with 4-pyrazoleboronic acid pinacol ester to generate 5-(1H-pyrazole-4-yl)pyridin-3-ol; A benzyl protecting group is attached to the N atom of the pyridine ring of the 5-(1H-pyrazol-4-yl)pyridin-3-ol using benzyl bromide; Catalytic hydrogenation yields 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol; Reaction with R1-Br to replace the H atom of the 1H-pyrazole ring of the 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol with R1; Reaction with R-4-methylbenzenesulfonate yields a compound having the structure of formula III; Structural Form III By retaining the benzyl protecting group, or by removing the benzyl protecting group and then attaching the R2 group, the piperidine ring compound having the structure of formula I is obtained; Structural Formula I Wherein, R is a C1-C10 substituted or unsubstituted alkyl, a C1-C6 substituted or unsubstituted cycloalkyl, a C6-C12 substituted or unsubstituted aryl, or a C4-C6 substituted or unsubstituted heteroaryl; R1 is an optionally substituted methoxyphenyl; R2 is H, a C1-C6 substituted or unsubstituted alkyl, a C1-C6 substituted or unsubstituted cycloalkyl, a C6-C12 substituted or unsubstituted aryl, or a C4-C6 substituted or unsubstituted heteroaryl.

[0007] Fourthly, this application provides the use of the piperidine cyclic compounds described in the first aspect and the pharmaceutically acceptable salts described in the second aspect in the preparation of medicaments for treating non-alcoholic fatty liver disease.

[0008] Fifthly, this application provides a drug for treating non-alcoholic fatty liver disease, prepared using the piperidine cyclic compound described in the first aspect or a pharmaceutically acceptable salt described in the second aspect.

[0009] The beneficial effects of this invention are: the piperidine cyclic compounds provided by this invention have an enhancing effect on the transcription of CPT1α, a key gene for fatty acid β-oxidation downstream of peroxisome proliferator-activated receptor α (PPARα).

[0010] Other features and advantages of this application will be set forth in the following description and will be apparent in part from the description or may be learned by practicing the application. The objectives and other advantages of this application will be realized and attained by way of the written description and the accompanying drawings. Attached Figure Description

[0011] Figure 1 This is a comparison chart showing the activity test results of piperidine cyclic compounds obtained in the embodiments of this application, intermediate products in the synthesis of piperidine cyclic compounds, and commercially available PPARα agonists against the CPT1α gene. Detailed Implementation

[0012] To make the objectives, technical solutions, and advantages of the embodiments of this disclosure clearer, the technical solutions of the embodiments of this disclosure are described clearly and completely below. Obviously, the described embodiments are only some, not all, of the embodiments of this disclosure. All other embodiments obtained by those skilled in the art based on the described embodiments of this disclosure without creative effort are within the scope of protection of this invention.

[0013] It should be understood that, without conflict, any and all embodiments of the present invention can be combined with technical features of any other embodiment or multiple other embodiments to obtain other embodiments. The present invention includes such combinations to obtain other embodiments.

[0014] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0015] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0016] The common structure of PPARα selective agonists consists of an aromatic ring and a carboxylic acid, with different spacer groups. The aromatic ring of the ligand interacts with the hydrophobic binding bag, and the acidic moiety forms hydrogen bonds with the amino acid at the active site, forming a roughly Y-shaped ligand binding site. Therefore, this application designs a Y-shaped structure. To improve the pharmacological properties of the drug, we chose to replace the flexible chain portion of pemafibrate with a piperidine ring commonly used in pharmaceutical intermediates.

[0017] This application provides a piperidine cyclic compound having the structure shown in structural formula I: Structural Formula I Wherein, R is a C1-C10 substituted or unsubstituted alkyl, a C1-C6 substituted or unsubstituted cycloalkyl, a C6-C12 substituted or unsubstituted aryl, or a C4-C6 substituted or unsubstituted heteroaryl; R1 is an optionally substituted methoxyphenyl; R2 is H, a C1-C6 substituted or unsubstituted alkyl, a C1-C6 substituted or unsubstituted cycloalkyl, a C6-C12 substituted or unsubstituted aryl, or a C4-C6 substituted or unsubstituted heteroaryl.

[0018] This piperidine cyclic compound can be synthesized via the following route: S1: 5-Bromopyridin-3-ol is reacted with 4-pyrazoleboronic acid pinacol ester to generate 5-(1H-pyrazole-4-yl)pyridin-3-ol.

[0019] S2: Benzyl protecting group is attached to the N atom of the pyridine ring of the 5-(1H-pyrazol-4-yl)pyridin-3-ol by benzyl bromide.

[0020] S3: Catalytic hydrogenation yields 1-benzyl-5-(1H-pyrazol-4-yl)piperidine-3-ol.

[0021] S4: Reacts with R1-Br to replace the H atom of the 1H-pyrazole ring of the 1-benzyl-5-(1H-pyrazol-4-yl)piperidine-3-ol with R1.

[0022] S5: Reaction with R-4-methylbenzenesulfonate to replace the H atom on the alcohol hydroxyl group with an R group, yielding a compound with structure III.

[0023] Structural Form III Benzyl is a substituted alkyl group, which meets the structure required by R2. Structural formula III is actually one embodiment of structural formula I.

[0024] Steps S1 to S5 are carried out according to the following reaction formula I.

[0025] Reaction I In step S1, Pd(dppf)Cl2 (1,1'-bis(diphenylphosphine)ferrocene palladium dichloride) is used as the catalyst.

[0026] The pyridine ring is highly stable, making direct reduction to piperidine using hydrogen and palladium on carbon very difficult and yielding low results. Step S2 involves a two-step catalytic hydrogenation process. First, sodium borohydride is used to open some unsaturated bonds, followed by complete reduction to piperidine using palladium on carbon. This reduces the reaction difficulty and increases the yield.

[0027] If the R2 group is to be replaced with another structure, proceed to step S6.

[0028] S6: Remove the benzyl protecting group to attach a H atom to the N atom on the piperidine ring of structural formula III, and then react with R2-Br to replace the H atom attached to the N atom on the piperidine ring with R2, to obtain the piperidine ring compound shown in structural formula I.

[0029] Step S6 is carried out according to the following reaction formula II.

[0030] Reaction formula II In this process, the benzyl protecting group is removed by mixing a compound with structural formula III with ammonium formate under a hydrogen atmosphere and reacting it with a palladium on carbon catalyst.

[0031] Preferably, R1 is one of the following groups:

[0032] R2 is one of the following groups: .

[0033] In a preferred embodiment, R has the structure shown in Formula II: Structural Form II Wherein, X is a secondary amino group, an oxygen atom, or a methylene group; R3 is H, a C1-C6 alkyl group, a C1-C6 cycloalkyl group, a C6-C12 substituted or unsubstituted aryl group, or a C4-C6 substituted or unsubstituted heteroaryl group; and R4 is a group containing an ester group or a carboxyl group.

[0034] Specifically, R3 is one of the following groups:

[0035] The above structure is connected at one end to the oxygen atom in structural formula I, and at the other end to X.

[0036] R4 is one of the following groups: .

[0037] Accordingly, step S5 has the following changes.

[0038] When X is a secondary amine group or an oxygen atom, step S5 proceeds according to the following reaction formula III.

[0039] Reaction Formula III First, the H atom on the hydroxyl group of the alcohol is replaced with the -R3-XH group by HX-R3-4-methylbenzenesulfonate. Then, it is reacted with R4-Br to replace the H atom of the -R3-XH group with the R4 group.

[0040] When X is a methylene group, step S5 proceeds according to the following reaction formula IV.

[0041] Reaction IV Compared to the case where X is a secondary amine group and an oxygen atom, the H atom of the -R3-XH group is replaced with a boric acid group.

[0042] The obtained piperidine ring compounds can be further prepared into pharmaceutically acceptable salts, such as hydrochloride, fumarate, succinate, phosphate, and methanesulfonate.

[0043] Example 1: Synthesis method of compound LYsc262

[0044] The synthesis steps of LY-sc7, as shown in the above reaction formula, are as follows: A mixture of 5-bromopyridin-3-ol (1 eq, 54.599 mmol), Pd(dppf)Cl2 (0.05 eq, 2.730 mmol), K2CO3 (1.5 eq, 81.898 mmol), and 4-pyrazoloboronic acid pinacol ester (1.2 eq, 65.518 mmol) in 1,4-dioxane (30.81 eq, 1682.194 mmol) and water (28.97 eq, 1664.971 mmol) is stirred at 100 °C under argon for 24 h, ensuring an anaerobic environment during sample addition. After the reaction is complete and cooled to room temperature, thin-layer chromatography is used to determine the completeness of the reaction. If the reaction is complete, the mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluted with DCM / MeOH (dichloromethane:methanol = 10:1), to give a brown solid with a yield of 45.28%. 1 H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 7.92 (s, 2H), 7.85 (s,1H), 7.32 (s, 1H).

[0045]

[0046] The synthesis steps of LY-sc9, as shown in the above reaction formula, are as follows: A mixture of 5-(1H-pyrazol-4-yl)-3-ol (1 eq, 31.851 mmol) and BnBr (benzyl bromide, 1.2 eq, 1.038 mmol) in MeCN (acetonitrile, 170.23 eq, 6942.365 mmol) is stirred overnight at 60 °C under hydrogen. The resulting mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluting with DCM / MeOH (5:1) to give a brown solid in 75.4% yield. 1 H NMR (400 MHz, Methanol-d4) δ 8.49 (s,1H), 8.15 (s, 2H), 7.83 (s, 1H), 7.69 (s, 1H), 7.50 (d, J = 5.9 Hz, 2H), 7.42(d, J = 6.3 Hz, 3H), 5.61 (s, 2H).

[0047]

[0048] The synthesis steps of LY-sc35, as shown in the above reaction formula, are as follows: A mixture of 1-benzyl-3-hydroxy-5-(1H-pyrazol-4-yl)pyridin-1-onium bromide (1 eq, 16.896 mmol) and NaBH4 (9 eq, 152.18 mmol) in MeOH (251.64 eq, 5643.864 mmol) is stirred overnight at room temperature under argon. The resulting mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give a yellow oil in 69.5% yield. 1 H NMR (400 MHz, Methanol-d4) δ 7.49 (s, 2H), 7.33 (d, J = 4.3 Hz, 4H), 7.29 – 7.23 (m, 1H), 6.56 (s,1H), 4.10 (s, 2H), 2.98 (s, 1H), 2.68 (d, J = 13.3 Hz, 1H), 2.54 (s, 1H), 2.20 (s, 1H).

[0049]

[0050] The synthesis steps of LY-sc45, as shown in the above reaction formula, are as follows: A mixture of 1-benzyl-5-(1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine-3-ol (1 eq, 10.692 mmol) and 10% Pd / C (0.1 eq, 1.069 mmol) in MeOH (438.89 eq, 5929.777 mmol) is stirred in hydrogen at room temperature for 6 h. The resulting mixture is filtered, and the filter cake is washed with DCM (dichloromethane, 3 times x 100 mL). The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give a colorless oil in 67.6% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.33 (s,2H), 7.28 – 7.15 (m, 5H), 3.91 (s, 1H), 3.50 (d, J = 3.8 Hz, 2H), 3.13 (t, J= 11.6 Hz, 1H), 2.94 (d, J = 9.3 Hz, 1H), 2.85 (d, J = 10.7 Hz, 1H), 2.19 (d,J = 11.2 Hz, 1H), 1.99 (dt, J = 22.0, 12.1 Hz, 2H), 1.43 (t, J = 12.8 Hz,1H).

[0051]

[0052] The synthesis steps of LY-sc105, as shown in the above reaction formula, are as follows: A mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), p-bromoanisole (1 eq), CuI (0.1 eq), Cs₂CO₃ (2 eq), and DMEDA (n,n-dimethylethylenediamine, 0.2 eq) in MeOH (0.7 eq) and H₂O (0.7 eq) is stirred at 150 °C under argon for 24 h. The resulting mixture is extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers are combined and dried over anhydrous sodium sulfate, the mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give a brownish-yellow oil in 90.9% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.53 (s, 1H), 7.45 (d, J = 8.3Hz, 3H), 7.23 (dd, J = 22.8, 6.3 Hz, 5H), 6.87 (d, J = 8.7 Hz, 2H), 3.75 (s,3H), 3.56 (d, J = 17.7 Hz, 2H), 3.19 (s, 1H), 2.92 (dd, J = 22.7, 12.5 Hz, 2H), 2.24 (d, J = 12.2 Hz, 1H), 2.04 (d, J = 18.5Hz, 1H), 2.00-1.89 (m, 1H),1.55-1.32 (m, 1H), 1.23-1.15 (m, 1H).

[0053]

[0054] As shown in the above reaction formula, the synthesis steps of LY-sc208 are as follows: 1-benzyl-5-(1-(4-methoxyphenyl)pyrazol-4-yl)piperidin-3-ol (1 eq, 2.67 mmol), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq, 2.8 mmol) and NaO t The mixture of Bu (sodium tert-butoxide, 1 eq, 2.67 mmol) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1) to give a brownish oily product in 48.3% yield. 1H NMR (400 MHz, Chloroform-d)δ 7.68 (dd, J = 16.8, 8.6 Hz, 2H), 7.58 (dd, J = 15.8, 8.0 Hz, 2H), 7.46 (t,J = 7.9 Hz, 2H), 7.31 (dd, J = 20.1, 11.6 Hz, 5H), 7.19 (s, 2H), 6.91 (dd, J= 25.9, 8.7 Hz, 2H), 4.07-3.86 (m, 1H), 3.76 (s, 2H), 3.71-3.45 (m, 3H), 3.29(d, J = 31.2 Hz, 2H), 3.12 – 2.94 (m, 1H), 2.37 (d, J = 22.1 Hz, 2H), 2.09 –1.89 (m, 2H).

[0055]

[0056] The synthesis steps of LY-sc247 are as follows: A mixture of 1-benzyl-3-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)-5-(3-nitrophenoxy)piperidine (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH (ethanol) and water is stirred at 78°C under argon for 2 h. The mixture is cooled to room temperature and filtered. The filter cake is washed with DCM (3 x 100 mL), and the resulting mixture is concentrated under reduced pressure. The resulting mixture is extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with EA (ethyl acetate, 3 x 100 mL). The organic layers are combined and dried over anhydrous sodium sulfate. The resulting mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give a brownish-red oil in 99.6% yield. 1H NMR (400 MHz, Chloroform-d)δ 7.53 (d, J = 5.5 Hz, 1H), 7.45 (d, J = 6.5 Hz, 3H), 7.27 (d, J = 14.9 Hz,5H), 7.19 (s, 1H), 6.87 (d, J = 8.3 Hz, 2H), 6.21 (dt, J = 18.7, 9.3 Hz, 3H), 3.76 (s, 3H), 3.57 (s, 2H), 3.31 – 3.18 (m, 2H), 2.98 (dd, J = 23.3, 12.3 Hz, 2H), 2.42 – 2.29 (m, 1H), 2.22 (d, J = 28.3 Hz, 1H), 1.99 (dt, J = 23.9, 14.0Hz, 2H).

[0057]

[0058] The synthesis steps of LY-sc249, as shown in the above reaction formula, are as follows: A mixture of 107 mmol of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline and methyl 2-bromobutyrate (50.6 mmol) in DMF is stirred at 60 °C under argon for 20 h. The mixture is cooled to room temperature and extracted. The resulting mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer is washed with brine (3 x 100 mL). The organic layers are combined and dried over anhydrous sodium sulfate. The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluting with PE / EA (petroleum ether: ethyl acetate = 3:1) to give a brownish-red oil in 27.3% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J =6.6 Hz, 1H), 7.50 – 7.41 (m, 3H), 7.26 (d, J = 4.3 Hz, 5H), 7.19 (s, 1H),6.99 – 6.92 (m, 1H), 6.88 (s, 1H), 6.22 (dd, J = 12.3, 8.4 Hz, 1H), 6.19 – 6.07 (m, 2H), 4.10 – 4.00 (m, 2H), 3.93 (s, 2H), 3.76 (s, 3H), 3.66 – 3.61(m, 3H), 3.56 (s, 1H), 3.28 – 3.18 (m, 1H), 3.00(d, J = 11.0 Hz, 1H), 1.97(s, 2H), 1.79 (d, J = 7.0 Hz, 1H), 1.74 – 1.68 (m, 1H), 1.19 (s, 2H), 0.91(dd, J = 7.3, 3.7 Hz, 3H).

[0059]

[0060] The synthesis steps of LY-sc262 are as follows: Methyl 2-((3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) are stirred at 50 °C under argon for 3 h. After cooling to room temperature, the pH is adjusted to acidic, and the resulting mixture is extracted. The mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers are combined and dried over anhydrous sodium sulfate. The resulting mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give a brownish-red oil in 92.6% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J =10.3 Hz, 1H), 7.46 – 7.38 (m, 3H), 7.23 (d, J = 31.9 Hz, 5H), 6.97 – 6.82 (m,3H), 6.18 (d, J = 31.4 Hz, 3H), 4.63 – 4.20 (m, 1H), 4.05 (q, J = 7.1 Hz,1H), 3.91 (d, J = 12.5 Hz, 1H), 3.75 (s, 3H), 3.63 (s, 1H), 3.52 (s, 1H), 3.18 (d, J = 10.5 Hz, 1H), 2.60 – 2.26 (m, 1H), 2.10 (d, J = 10.9 Hz, 1H), 1.99 (d, J = 12.9 Hz, 2H), 1.85 (d, J = 24.8 Hz, 2H), 1.63 – 1.42 (m, 1H), 0.96 (s, 3H).

[0061] Example 2: Synthesis method of compound 2

[0062] As per the above reaction formula, a mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), 1-bromo-4-(prop-2-yn-1-yloxy)benzene (1 eq), CuI (0.1 eq), Cs₂CO₃ (2 eq), and DMEDA (0.2 eq) in MeOH (0.7 eq) and H₂O (0.7 eq) was stirred at 150 °C under argon for 24 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0063]

[0064] As shown in the above reaction formula, 1-benzyl-5-(1-(4-(prop-2-yn-1-yloxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-ol (1 eq), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO tThe mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0065]

[0066] As per the above reaction formula, a mixture of 1-benzyl-3-(3-nitrophenoxy)-5-(1-(4-(prop-2-yn-1-yloxy)phenyl)-1H-pyrazol-4-yl)piperidine (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 78 °C under argon for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 x 100 mL), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0067]

[0068] As shown in the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-(prop-2-yn-1-yloxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF (N,N-dimethylformamide) was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0069]

[0070] As shown in the above reaction formula, a mixture of methyl 2-((3-((1-benzyl-5-(1-(4-(prop-2-yn-1-oxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 2.

[0071] Example 3: Synthesis method of compound 3

[0072] As per the above reaction formula, a mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), 5-bromo-3-methoxybenzyl-1,2-diol (1 eq), CuI (0.1 eq), Cs₂CO₃ (2 eq), and DMEDA (0.2 eq) in MeOH (0.7 eq) and H₂O (0.7 eq) was stirred at 150 °C under argon for 16 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0073]

[0074] As shown in the above reaction formula, 5-(4-(1-benzyl-5-hydroxypiperidin-3-yl)-1H-pyrazole-1-yl)-3-methoxyphenyl-1,2-diol (1 eq), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO are reacted. t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0075]

[0076] As per the above reaction formula, a mixture of 5-(4-(1-benzyl-5-(3-nitrophenoxy)piperidin-3-yl)-1H-pyrazole-1-yl)-3-methoxyphenyl-1,2-diol (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 78 °C under argon for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 x 100 mL), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0077]

[0078] As per the above reaction formula, a mixture of 5-(4-(5-(3-aminophenoxy)-1-benzylpiperidin-3-yl)-1H-pyrazole-1-yl)-3-methoxyphenyl-1,2-diol (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0079]

[0080] As shown in the above reaction formula, a mixture of methyl 2-((3-((1-benzyl-5-(1-(3,4-dihydroxy-5-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give compound 3.

[0081] Example 4: Synthesis method of compound 4:

[0082] As per the above reaction formula, a mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), 2-bromo-1,4-dimethoxybenzene (1 eq), CuI (0.1 eq), Cs₂CO₃ (2 eq), and DMEDA (0.2 eq) in MeOH (0.7 eq) and H₂O (0.7 eq) was stirred at 150 °C under argon for 16 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0083]

[0084] As shown in the above reaction formula, 1-benzyl-5-(1-(2,5-dimethoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-ol (1 eq), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO are reacted. t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0085]

[0086] As per the above reaction formula, a mixture of 1-benzyl-3-(1-(2,5-dimethoxyphenyl)-1H-pyrazol-4-yl)-5-(3-nitrophenoxy)piperidine (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 78 °C under argon for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 x 100 mL), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0087]

[0088] As per the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(2,5-dimethoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0089]

[0090] As shown in the above reaction formula, a mixture of methyl 2-(3-((1-benzyl-5-(1-(2,5-dimethoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 4.

[0091] Example 5: Synthesis method of compound 5:

[0092] As per the above reaction formula, a mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), 1-bromo-4-(chloromethoxy)benzene (1 eq), CuI (0.1 eq), Cs₂CO₃ (2 eq), and DMEDA (0.2 eq) in MeOH (0.7 eq) and H₂O (0.7 eq) was stirred at 150 °C under argon for 16 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0093]

[0094] As shown in the above reaction formula, 1-benzyl-5-(1-(4-(chloromethoxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-ol (1 eq), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaOt The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0095]

[0096] As per the above reaction formula, a mixture of 1-benzyl-3-(1-(4-(chloromethoxy)phenyl)-1H-pyrazol-4-yl)-5-(3-nitrophenoxy)piperidine (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 60 °C under argon for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 x 100 mL), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0097]

[0098] As per the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-(chloromethoxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. The mixture was cooled to room temperature and extracted. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0099]

[0100] As shown in the above reaction formula, a mixture of methyl 2-((3-((1-benzyl-5-(1-(4-(chloromethoxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 5.

[0101] Example 6: Synthesis method of compound 6:

[0102] As per the above reaction formula, a mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), 5-bromo-2,3-dimethoxyphenol (1 eq), CuI (0.1 eq), Cs₂CO₃ (2 eq), and DMEDA (0.2 eq) in MeOH (0.7 eq) and H₂O (0.7 eq) was stirred at 150 °C under argon for 16 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0103]

[0104] As shown in the above reaction formula, 1-benzyl-5-(1-(3-hydroxy-4,5-dimethoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-ol (1 eq), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO are reacted. t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and washed with DCM / MeOH (30:1).

[0105]

[0106] As per the above reaction formula, a mixture of 5-(4-(1-benzyl-5-(3-nitrophenoxy)piperidin-3-yl)-1H-pyrazole-1-yl)-2,3-dimethoxyphenol (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 60 °C under argon for 2 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with DCM (3 x 100 mL). The resulting mixture was concentrated under reduced pressure. The extracted mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0107]

[0108] As per the above reaction formula, a mixture of 5-(4-(5-(3-aminophenoxy)-1-benzylpiperidin-3-yl)-1H-pyrazole-1-yl)-2,3-dimethoxyphenol (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0109]

[0110] As shown in the above reaction formula, a mixture of methyl 2-((3-((1-benzyl-5-(1-(3-hydroxy-4,5-dimethoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 6.

[0111] Example 7: Synthesis method of compound 7:

[0112] As shown in the above reaction formula, 1-benzyl-5-(1-(4-methoxyphenyl)pyrazol-4-yl)piperidin-3-ol (1 eq), 4-nitrobenzene-4-methylbenzenesulfonate (1.2 eq) and NaO are reacted. t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0113]

[0114] As per the above reaction formula, a mixture of 1-benzyl-3-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)-5-(4-nitrophenoxy)piperidine (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 60 °C under argon for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 x 100 mL), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0115]

[0116] As per the above reaction formula, a mixture of 4-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. The mixture was cooled to room temperature and extracted. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0117]

[0118] As shown in the above reaction formula, a mixture of methyl 2-(4-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 3 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 7.

[0119] Example 8: Synthesis method of compound 8:

[0120] As shown in the above reaction formula, 1-benzyl-5-(1-(4-methoxyphenyl)pyrazol-4-yl)piperidin-3-ol (1 eq), 4-methyl-3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0121]

[0122] As per the above reaction formula, a mixture of 1-benzyl-3-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)-5-(4-methyl-3-nitrophenoxy)piperidine (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 60 °C under argon for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with DCM (3 x 100 mL), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0123]

[0124] As per the above reaction formula, a mixture of 5-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)-2-methylaniline (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0125]

[0126] As per the above reaction formula, a mixture of methyl 2-((5-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)-2-methylphenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give compound 8.

[0127] Example 9: Synthesis method of compound 9:

[0128] As shown in the above reaction formula, 1-benzyl-5-(1-(4-methoxyphenyl)pyrazol-4-yl)piperidin-3-ol (1 eq), 2-aminophenyl 4-methylbenzenesulfonic acid ester (1.2 eq), and NaO are reacted. t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0129]

[0130] As per the above reaction formula, a mixture of 2-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0131]

[0132] As shown in the above reaction formula, a mixture of methyl 2-((2-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 9.

[0133] Example 10: Synthesis method of compound 10:

[0134] As shown in the above reaction formula, 1-benzyl-5-(1-(4-methoxyphenyl)pyrazol-4-yl)piperidin-3-ol (1 eq), 2-formyl-4-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO t The mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1).

[0135]

[0136] As per the above reaction formula, a mixture of 2-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)-5-nitrobenzaldehyde (1 eq), Fe powder (6 eq), and NH4Cl (2 eq) in EtOH and water was stirred at 60 °C under argon for 2 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with DCM (3 x 100 mL). The resulting mixture was concentrated under reduced pressure. The extracted mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0137]

[0138] As per the above reaction formula, a mixture of 5-amino-2-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)benzaldehyde (2 eq) and methyl 2-bromobutyrate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. The mixture was cooled to room temperature and extracted. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0139]

[0140] As shown in the above reaction formula, a mixture of methyl 2-((4-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)-3-formylphenyl)amino)butyrate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 10.

[0141] Example 11: Synthesis method of compound 11:

[0142] As per the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and ethyl 2-bromopentanoate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. The mixture was cooled to room temperature and extracted. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0143]

[0144] As shown in the above reaction formula, a mixture of ethyl 2-((3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)valerate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 11.

[0145] Example 12 Synthesis method of compound 12:

[0146] As per the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromo-2-cyclopropylacetate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0147]

[0148] As shown in the above reaction formula, a mixture of methyl 2-((3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)-2-cyclopropylacetate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 12.

[0149] Example 13: Synthesis method of compound 13:

[0150] As per the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and methyl 2-bromo-2-cyclobutylacetate (1 eq) in DMF was stirred at 60 °C under argon for 20 h. The mixture was cooled to room temperature and extracted. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layer was washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0151]

[0152] As shown in the above reaction formula, a mixture of methyl 2-((3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)-2-cyclobutylacetate (1 eq) and NaOH (1.2 eq) in MeOH and H2O (MeOH : H2O = 3 : 1) was stirred at 50 °C under argon for 16 h. After cooling to room temperature, the pH was adjusted to acidic, and the resulting mixture was extracted. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), to give compound 13.

[0153] Example 14 Synthesis method of compound 14:

[0154] As per the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2 eq) and 2-bromo-4-ethoxy-4-oxobutyric acid (1 eq) in DMF was stirred at 60 °C under argon for 20 h. After cooling to room temperature, extraction was performed. The resulting mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x 100 mL), and the organic layers were washed with brine (3 x 100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give compound 14.

[0155] Example 15: Synthesis method of compound 15:

[0156] As shown in the above reaction formula, a mixture of 2-((3-((5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyric acid (2 eq), 3-bromophenol (1 eq), CuI (0.1 eq), K2CO3 (1.5 eq), and DMEDA (0.2 eq) in DMF (0.7 eq) was stirred at 90 °C under argon for 24 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give compound 15.

[0157] Example 16: Synthesis method of compound 16:

[0158] As per the above reaction formula, a mixture of 2-((3-((5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyric acid (2 eq), 3-(bromomethyl)phenol (1 eq), CuI (0.1 eq), K2CO3 (1.5 eq), and DMEDA (0.2 eq) in DMF (0.7 eq) was stirred at 90 °C under argon for 24 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give compound 16.

[0159] Example 17 Synthesis method of compound 17:

[0160] As per the above reaction formula, a mixture of 2-((3-((5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyric acid (2 eq), 1-(2-bromoethyl)-4-methoxypiperidine (1 eq), CuI (0.1 eq), K2CO3 (1.5 eq), and DMEDA (0.2 eq) in DMF (0.7 eq) was stirred at 90 °C under argon for 24 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give compound 17.

[0161] Example 18: Synthesis method of compound 18:

[0162] As shown in the above reaction formula, a mixture of 2-((3-((5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butyric acid (2 eq), 3-hydroxybenzoic acid (1 eq), CuI (0.1 eq), K2CO3 (1.5 eq), and DMEDA (0.2 eq) in DMF (0.7 eq) was stirred at 90 °C under argon for 24 h. The resulting mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with DCM (3 x 100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give compound 18.

[0163] Cell activity assays were performed on the compounds prepared in the embodiments of this application. The experimental principles and methods are as follows.

[0164] CPT1α is the gene encoding carnitine palmitoyltransferase I. Carnitine palmitoyltransferase I is a key enzyme involved in the β-oxidation of long-chain fatty acids, primarily functioning in the liver and muscles. It catalyzes the transfer of long-chain fatty acids from acyl-CoA to carnitine, allowing the fatty acids to cross the inner mitochondrial membrane into the mitochondrial matrix for β-oxidation. This step is the initiation step in the mitochondrial oxidation of long-chain fatty acids.

[0165] PPARα exerts its effects by recognizing and binding to peroxisome proliferator response elements (PPREs) located in the promoter regions of target genes. PPARα target genes associated with fatty acid oxidation are primarily regulated in a PPRE-dependent manner. PPARα can stimulate the transcription of PPARα target genes in the fatty acid β-oxidation pathway, including CPT1α. In the liver, CPT1α and PDK4 gene expression are induced by PPARα, particularly under conditions of starvation, a high-fat diet, and the presence of PPARα ligands. PPARα has a binding site in the second intron of the rat CPT1α gene, and studies have shown that WY14643 (a PPARα agonist) and long-chain fatty acids induce CPT1α gene expression through this site. PPARα plays a crucial role in lipid metabolism and energy balance by directly regulating CPT1α gene expression and enhancing fatty acid oxidation. The activity and expression level of CPT1α are directly influenced by PPARα, and both work together in metabolic regulation to maintain energy homeostasis. Activity assays targeting the CPT1α gene confirmed that piperidine cyclic compounds have an agonistic effect on PPARα.

[0166] HepG2 is a human liver cancer cell line, cultured in MEM medium containing 1% penicillin / streptomycin and 10% FBS.

[0167] HepG2 cells were seeded in 12-well plates at a density of 1.5 x 10⁵ cells / well in 1 ml of culture medium. After 24 h, the medium was replaced with medium containing either a compound (10 μM) or DMSO and cultured for another 24 h. Total RNA was extracted using Trizol. The 10 μM "compound" refers to LY-sc105, LY-sc208, LY-sc247, LY-sc249, LY-sc262 prepared according to the embodiments of this application, or commercially available WY14643. Only one of these compounds was used in each group (the DMSO group did not contain any of the above compounds).

[0168] Total RNA was extracted using Trizol reagent (Yeasen), reverse transcribed using 5xABScript III RT Master Mix (Abclonal), and real-time PCR was performed using 2xSYBR Green Fast qPCR Mix (Abclonal). All results were normalized to GAPDH expression (with glyceraldehyde-3-phosphate dehydrogenase as an internal control protein) and calculated using the 2-(ΔΔCt) method. Human cpt1α 5'-TCCAGTTGGCTTATCGTGGTG-3' (sense) and 5'-TCCAGAGTCCGATTGATTTTTGC-3' (antisense) and human GAPDH 5'-GGAGCGAGATCCCTCCAAAAT-3' (sense) and 5'-GGCTGTTGTCATACTTCTCATGG-3' (antisense) were used as primers for RT-qPCR experiments.

[0169] This experiment used RT-PCR to detect the agonistic effects of LY-sc105, LY-sc208, LY-sc247, LY-sc249, and LY-sc262 on CPT1α. The experimental results are as follows: Figure 1 As shown. Bioactivity results indicate that LY-sc247, LY-sc249, and LY-sc262 can enhance CPT1α transcription. The process can be reasonably considered as follows: the piperidine cyclic compounds of this application have an agonistic effect on the PPARα receptor, thereby enhancing CPT1α gene expression under PPARα regulation. This demonstrates that the piperidine cyclic compounds obtained in this application, or their pharmaceutically acceptable salts, have the potential to treat non-alcoholic fatty liver disease and can be used to prepare drugs for treating non-alcoholic fatty liver disease, for example, directly as components of pharmaceutical products or as intermediates in drug preparation.

[0170] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0171] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A piperidine cyclic compound, characterized in that, It has the structure shown in structural formula I: ； Structural Formula I; R1 is: ; R2 is: ; R has the structure shown in structural formula II: ； Structural Formula II; Where X is a secondary amino group; R3 is: ; R4 is a hydrogen atom or one of the following groups: 。 2. A pharmaceutically acceptable salt of the piperidine cyclic compound of claim 1.

3. A method for synthesizing piperidine cyclic compounds, characterized in that, Includes the following steps: 5-Bromopyridin-3-ol was reacted with pinacol 4-pyrazolboronic acid to generate 5-(1H-pyrazol-4-yl)pyridin-3-ol; A benzyl protecting group is attached to the N atom of the pyridine ring of the 5-(1H-pyrazol-4-yl)pyridin-3-ol using benzyl bromide; Catalytic hydrogenation yields 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol; Reaction with R1-Br to replace the H atom of the 1H-pyrazole ring of the 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol with R1; Reaction with R-4-methylbenzenesulfonate yields a compound having the structure of formula III; ； Structural Form III; Where R1 is: ; R has the structure shown in structural formula II: ； Structural Formula II; Where X is a secondary amino group; R3 is: R4 is a hydrogen atom or one of the following groups: 。 4. Use of the piperidine cyclic compound of claim 1 and the pharmaceutically acceptable salt of claim 2 in the preparation of a medicament for treating non-alcoholic fatty liver disease.

5. A drug for treating non-alcoholic fatty liver disease, characterized in that, It is prepared using the piperidine cyclic compound of claim 1 or the pharmaceutically acceptable salt of claim 2.

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