Piperidine ring compound as well as synthesis method, pharmaceutically acceptable salt and application thereof

Abstract

The invention discloses a piperidine ring compound as well as a synthesis method, pharmaceutically acceptable salt and application thereof, and belongs to the technical field of medicines, and the piperidine ring compound shows that the piperidine ring compound has a transcription enhancing effect on a fatty acid beta-oxidation key gene-CPT1 alpha at the downstream of a peroxisome proliferator-activated receptor alpha (PPAR alpha), and can be used for preparing a medicine for preventing and treating the fatty acid beta-oxidation key gene-CPT1 alpha. The compound is expected to be used as a potential medicine for treating the non-alcoholic fatty liver disease.

Description

Technical Field

[0001] The invention relates to a piperidine ring compound and a synthesis method thereof, a pharmaceutically acceptable salt and application thereof, and belongs to the technical field of medicine. Background Art

[0002] Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play a key role in the transcriptional regulation of glucose and lipid metabolism. The PPAR family consists of three members: PPARα (NR1C1), PPARδ (NR1C2), and PPARγ, which are expressed in different tissues and perform specific biological functions. Specifically, activation of PPARα mainly regulates fatty acid oxidation (FAO), reduces serum triglyceride levels, and maintains 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 the development of new therapeutics for dyslipidemia, metabolic syndrome, diabetes, non-alcoholic fatty liver disease (NAFLD), and its related cardiovascular complications. In addition, experiments and studies have also shown that PPARα has potential therapeutic effects in immune regulation, anti-inflammatory and neurodegenerative diseases. Therefore, it is particularly urgent to develop a drug that can specifically activate PPARα to improve dyslipidemia, and the drug should avoid causing adverse reactions such as weight gain, edema or activating other PPAR subtypes. Summary of the invention

[0003] The present invention provides a piperidine ring compound and a synthesis method thereof, a pharmaceutically acceptable salt and application thereof, which are intended to overcome the challenges faced by agonists targeting peroxisome proliferator-activated receptor α (PPARα) in the prior art, including the scarcity of drug types, low selectivity, limited agonist activity and insufficient bioavailability.

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

[0005] In a second aspect, the present application provides a pharmaceutically acceptable salt of the piperidine ring compound described in the first aspect.

[0006] In a third aspect, the present application provides a method for synthesizing a piperidine ring compound, comprising the following steps: 5-bromopyridin-3-ol is reacted with 4-pyrazoleboronic acid pinacol ester to generate 5-(1H-pyrazol-4-yl)pyridin-3-ol; Using benzyl bromide to attach a benzyl protecting group to the N atom on the pyridine ring of the 5-(1H-pyrazol-4-yl)pyridin-3-ol; Catalytic hydrogenation to obtain 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol; Reacting 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; reacting with R-4-methylbenzenesulfonate to obtain a compound having a structure of formula III; Structural formula Ⅲ Retaining the benzyl protecting group, or removing the benzyl protecting group and then attaching the R2 group, to obtain the piperidine ring compound having the structure of formula I; Structural formula Ⅰ Wherein, R is C1~C10 substituted or unsubstituted alkyl, C1~C6 substituted or unsubstituted cycloalkyl, C6~C12 substituted or unsubstituted aryl or C4~C6 substituted or unsubstituted heteroaryl; R1 is optionally substituted methoxyphenyl; R2 is H, C1~C6 substituted or unsubstituted alkyl, C1~C6 substituted or unsubstituted cycloalkyl, C6~C12 substituted or unsubstituted aryl or C4~C6 substituted or unsubstituted heteroaryl.

[0007] In a fourth aspect, the present application provides use of the piperidine ring compound described in the first aspect and the pharmaceutically acceptable salt described in the second aspect in the preparation of a drug for treating non-alcoholic fatty liver disease.

[0008] In a fifth aspect, the present application provides a drug for treating non-alcoholic fatty liver disease, which is prepared using the piperidine ring compound described in the first aspect or the pharmaceutically acceptable salt described in the second aspect.

[0009] The beneficial effect of the present invention is that the piperidine ring compound provided by the present invention has the effect of enhancing 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 the present application will be described in the following description, and partly become apparent from the description, or be understood by practicing the present application. The purpose and other advantages of the present application can be realized and obtained through the written description and the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 It is a comparison chart of the activity test results of the piperidine ring compound prepared in the examples of the present application, the intermediate product in the process of synthesizing the piperidine ring compound, and the commercially available PPARα agonist on the CPT1α gene. DETAILED DESCRIPTION

[0012] In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure clearer, the technical solution of the embodiments of the present disclosure is clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0013] It should be understood that, under the premise of no conflict, any and all embodiments of the present invention can be combined with the technical features in any other embodiment or multiple other embodiments to obtain another embodiment. The present invention includes such a combination to obtain another embodiment.

[0014] In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds. When substituents are described by conventional chemical formulas written from left to right, the substituents also include 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 belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0016] The common structure of PPARα selective agonists is composed of an aromatic ring and a carboxylic acid, with different spacers. The aromatic ring of the ligand interacts with the hydrophobic binding pocket, and the acidic part forms hydrogen bonds with the amino acid in the active site, forming a roughly Y-shaped ligand binding site. Therefore, this application designs a Y-shaped structure. In order to improve the pharmacology of the drug, we chose to replace the intermediate flexible chain of Pemabet with a piperidine ring commonly used in drug intermediates.

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

[0018] The piperidine ring compound can be synthesized by the following route: S1: 5-bromopyridin-3-ol is reacted with 4-pyrazoleboronic acid pinacol ester to generate 5-(1H-pyrazol-4-yl)pyridin-3-ol.

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

[0020] S3: catalytic hydrogenation to obtain 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol.

[0021] S4: reacting 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.

[0022] S5: react with R-4-methylbenzenesulfonate to replace the H atom on the alcoholic hydroxyl group with an R group to obtain a compound having a structure of formula III.

[0023] Structural formula Ⅲ Benzyl is a substituted alkyl group and 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 formula Ⅰ In step S1, Pd(dppf)Cl2 (1,1'-bis(diphenylphosphinoferrocene)palladium dichloride) is used as a catalyst.

[0026] The pyridine ring is very stable, and it is very difficult to directly reduce it to piperidine using hydrogen and palladium carbon, and the yield is also very low. In step S2, catalytic hydrogenation is performed in two steps. First, sodium borohydride is used to open some unsaturated bonds, and then palladium carbon is used to completely reduce it to piperidine, which reduces the difficulty of the reaction and improves the yield.

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

[0028] S6: removing the benzyl protecting group so that the N atom on the piperidine ring of structural formula III is connected to the H atom, and then reacting with R2-Br so that R2 replaces the H atom connected to the N atom on the piperidine ring 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 When removing the benzyl protecting group, the compound having the structural formula III is mixed with ammonium formate under a hydrogen atmosphere and reacted with a palladium-carbon catalyst to obtain the compound.

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

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

[0033] In a preferred embodiment, R has a structure shown in formula II: Structural formula Ⅱ Wherein, X is a secondary amine 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 an ester group or a carboxyl group-containing group.

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

[0035] Any end of the above structure is connected to the oxygen atom in structural formula I, and the other end is connected 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 is carried out according to the following reaction formula III.

[0039] Reaction formula III First, the H atom on the alcohol hydroxyl group is replaced by a -R3-XH group with HX-R3-4-methylbenzenesulfonate, and then it reacts with R4-Br to replace the H atom of the -R3-XH group with an R4 group.

[0040] When X is methylene, step S5 is carried out according to the following reaction formula IV.

[0041] Reaction Formula IV Compared with the above case where X is a secondary amine group or an oxygen atom, the H atom of the -R3-XH group is changed to a boronic acid group.

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

[0043] Example 1 Synthesis of Compound LYsc262

[0044] As shown in the above reaction formula, the synthesis steps of LY-sc7 are as follows: 5-bromopyridin-3-ol (1eq, 54.599mmol), Pd(dppf)Cl2 (0.05eq, 2.730mmmol), K2CO3 (1.5eq, 81.898mmol) and 4-pyrazoleboronic acid pinacol ester (1.2eq, 65.518mmol) in 1,4-dioxane (30.81eq, 1682.194mmol) and water (28.97eq, 1664.971mmol) were stirred at 100℃ under argon for 24h. When adding the sample, pay attention to control the oxygen-free environment. After the reaction is completed, cool to room temperature and use thin layer chromatography to detect whether the reaction is complete. If the reaction is complete, the resulting mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography using DCM / MeOH (dichloromethane:methanol=10:1) as eluent to obtain 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] As shown in the above reaction formula, the synthesis steps of LY-sc9 are as follows: a mixture of 5-(1H-pyrazol-4-yl)-3-ol (1eq, 31.851mmol) and BnBr (benzyl bromide, 1.2eq, 1.038mmol) in MeCN (acetonitrile, 170.23eq, 6942.365mmol) was stirred at 60°C under hydrogen overnight. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (5:1), and a brown solid was obtained with a yield of 75.4%. 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] As shown in the above reaction formula, the synthesis steps of LY-sc35 are as follows: A mixture of 1-benzyl-3-hydroxy-5 (1H-pyrazol-4-yl) pyridin-1-ium bromide (1 eq, 16.896 mmol) and NaBH4 (9 eq, 152.18 mmol) in MeOH (251.64 eq, 5643.864 mmol) was stirred at room temperature under argon overnight. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), and a yellow oil was obtained with a yield of 69.5%. 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] As shown in the above reaction formula, the synthesis steps of LY-sc45 are as follows: A mixture of 1-benzyl-5-(1H-pyrazol-4-yl)-1, 2, 3, 6-tetrahydropyridine-3-ol (1eq, 10.692mmol) and 10% Pd / C (0.1eq, 1.069mmol) in MeOH (438.89eq, 5929.777mmol) was stirred in hydrogen at room temperature for 6h. The resulting mixture was filtered and the filter cake was washed with DCM (dichloromethane, 3 times x 100 mL). The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), and a colorless oil was obtained with a yield of 67.6%. 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] As shown in the above reaction formula, the synthesis steps of LY-sc105 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) 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 resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to obtain a brown oil with a yield of 90.9%. 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 A mixture of Bu (sodium tert-butoxide, 1 eq, 2.67 mmol) in MeCN was stirred at 80 °C under argon for 16 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 residue was purified by silica gel column chromatography, eluting with DCM / MeOH (30:1) to give a brown oil in a yield of 48.3%. 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] As shown in the above reaction formula, 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 was stirred at 78°C under argon for 2 h. The mixture was cooled to room temperature and filtered, and the filter cake was washed with DCM (3 x 100 mL), and the mixture was concentrated under reduced pressure. The mixture was extracted, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (ethyl acetate, 3 x 100 mL), the organic layers were combined and dried with anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1), and a brown oil was obtained with a yield of 99.6%. 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] As shown in the above reaction formula, the synthesis steps of LY-sc249 are as follows: A mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (107mmol) and methyl 2-bromobutyrate (50.6mmol) in DMF was stirred at 60°C under argon for 20h. Cool to room temperature for extraction, the extracted mixture was neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with EA (3 x100 mL), the organic layer was washed with brine (3 x100 mL), the organic layers were combined and dried over anhydrous sodium sulfate, the obtained mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with PE / EA (petroleum ether: ethyl acetate = 3:1) to obtain a brown oil with a yield of 27.3%. 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] As shown in the above reaction formula, the synthesis steps of LY-sc262 are as follows: A mixture of methyl 2-((3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)phenyl)amino)butanoate (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, 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, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to obtain a brown oil with a yield of 92.6%. 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 of Compound 2

[0062] As in the above reaction, 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 resulting 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 in the above reaction, 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 tA 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 and 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 using DCM / MeOH (30:1) as eluent.

[0065]

[0066] As in the above reaction, 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, and the filter cake was washed with DCM (3 x 100 mL). The mixture was concentrated under reduced pressure. The 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 mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0067]

[0068] As 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 (2eq) and methyl 2-bromobutyrate (1eq) in DMF (N,N-dimethylformamide) was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to give compound 2.

[0071] Example 3 Synthesis of Compound 3

[0072] As in the above reaction, a mixture of 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol (1.5 eq), 5-bromo-3-methoxybenzene-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 resulting 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-pyrazol-1-yl)-3-methoxybenzene-1,2-diol (1 eq), 3-nitrophenyl-4-methylbenzenesulfonate (1.2 eq) and NaO t A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0075]

[0076] As in the above reaction, a mixture of 5-(4-(1-benzyl-5-(3-nitrophenoxy)piperidin-3-yl)-1H-pyrazol-1-yl)-3-methoxybenzene-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, and the filter cake was washed with DCM (3 x 100 mL). The mixture was concentrated under reduced pressure. The 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 mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0077]

[0078] As in the above reaction formula, a mixture of 5-(4-(5-(3-aminophenoxy)-1-benzylpiperidin-3-yl)-1H-pyrazol-1-yl)-3-methoxybenzene-1,2-diol (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 for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, the resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to give compound 3.

[0081] Example 4 Synthesis of Compound 4:

[0082] As in the above reaction, 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 resulting 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 t A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0085]

[0086] As in the above reaction, 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. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), and the mixture was concentrated under reduced pressure. The 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, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0087]

[0088] As in the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(2,5-dimethoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2eq) and methyl 2-bromobutyrate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, the resulting mixture was concentrated under reduced pressure, and 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 in the above reaction, 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 resulting 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 A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0095]

[0096] As in the above reaction, 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. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), and the mixture was concentrated under reduced pressure. The 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, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0097]

[0098] As in the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-(chloromethoxy)phenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2eq) and methyl 2-bromobutyrate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, 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 5.

[0101] Example 6 Synthesis method of compound 6:

[0102] As in the above reaction, 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 resulting 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 t A mixture of Bu (1 eq) in MeCN was stirred at 80 °C under argon for 16 h. The mixture was cooled to room temperature and 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, washing with DCM / MeOH (30:1).

[0105]

[0106] As in the above reaction, a mixture of 5-(4-(1-benzyl-5-(3-nitrophenoxy)piperidin-3-yl)-1H-pyrazol-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. The mixture was cooled to room temperature and filtered, and the filter cake was washed with DCM (3 x 100 mL). The mixture was concentrated under reduced pressure. The 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 mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0107]

[0108] As in the above reaction formula, a mixture of 5-(4-(5-(3-aminophenoxy)-1-benzylpiperidin-3-yl)-1H-pyrazol-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. The mixture was cooled to room temperature for extraction, and the extracted 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, and the obtained mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1).

[0109]

[0110] As 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)butanoate (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, 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, 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 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 t A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0113]

[0114] As in the above reaction, 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. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), and the mixture was concentrated under reduced pressure. The 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, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0115]

[0116] As in the above reaction formula, a mixture of 4-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2eq) and methyl 2-bromobutyrate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, the resulting mixture was concentrated under reduced pressure, and 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 A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0121]

[0122] As in the above reaction, 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. After cooling to room temperature, the mixture was filtered, the filter cake was washed with DCM (3 x 100 mL), and the mixture was concentrated under reduced pressure. The 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, the 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 in the above reaction formula, a mixture of 5-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)-2-methylaniline (2eq) and methyl 2-bromobutyrate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 in 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)butanoate (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, 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, 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), 4-methylbenzenesulfonic acid-2-aminophenyl ester (1.2 eq) and NaO t A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0129]

[0130] As in the above reaction formula, a mixture of 2-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2eq) and methyl 2-bromobutyrate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, 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 9.

[0133] Example 10 Synthesis 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 A 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 and 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 using DCM / MeOH (30:1) as eluent.

[0135]

[0136] As in the above reaction formula, a mixture of 2-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)-5-nitrobenzaldehyde (1eq), Fe powder (6eq) and NH4Cl (2eq) in EtOH and water was stirred at 60°C under argon for 2h. The mixture was cooled to room temperature and filtered, and the filter cake was washed with DCM (3 x 100 mL). The mixture was concentrated under reduced pressure. The 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 mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1).

[0137]

[0138] As in 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 (2eq) and methyl 2-bromobutyrate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)butanoate (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, 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, 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 10.

[0141] Example 11 Synthesis method of compound 11:

[0142] As in the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2eq) and ethyl 2-bromovalerate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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)pentanoate (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, 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, 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 11.

[0145] Example 12 Synthesis of Compound 12:

[0146] As in the above reaction formula, a mixture of 3-((1-benzyl-5-(1-(4-methoxyphenyl)-1H-pyrazol-4-yl)piperidin-3-yl)oxy)aniline (2eq) and methyl 2-bromo-2-cyclopropylacetate (1eq) in DMF was stirred at 60°C under argon for 20h. The mixture was cooled to room temperature for extraction, and the extracted 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 obtained 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 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, 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, 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 12.

[0149] Example 13 Synthesis method of compound 13:

[0150] As in 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 for extraction, and the extracted 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 obtained 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 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, 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, 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 13.

[0153] Example 14 Synthesis of Compound 14:

[0154] As in 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-oxobutanoic acid (1 eq) in DMF was stirred at 60 °C under argon for 20 h. The mixture was cooled to room temperature for extraction, and the extracted 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, and the obtained mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to obtain compound 14.

[0155] Example 15 Synthesis method of compound 15:

[0156] As 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, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain compound 15.

[0157] Example 16 Synthesis method of compound 16:

[0158] As 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-(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, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain compound 16.

[0159] Example 17 Synthesis method of compound 17:

[0160] As 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), 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, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain compound 17.

[0161] Example 18 Synthesis method of compound 18:

[0162] As 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, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to obtain compound 18.

[0163] The cell activity test was performed on the compounds prepared in the examples of the present application, and the experimental principle and method are as follows.

[0164] CPT1α is a gene encoding carnitine palmitoyltransferase Ⅰ. Carnitine palmitoyltransferase Ⅰ is a key enzyme involved in the β-oxidation of long-chain fatty acids, mainly in the liver and muscles. It catalyzes the transfer of long-chain fatty acids from acyl-CoA to carnitine so that the fatty acids can pass through the inner mitochondrial membrane and enter the mitochondrial matrix for β-oxidation. This step is the starting step for 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 region of target genes. PPARα target genes related to fatty acid oxidation are mainly regulated by PPREs binding-dependent regulation. 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, especially in the presence of starvation, high-fat diet, and PPARα ligands. PPARα has a binding site in the second intron of the rat CPT1α gene. Studies have shown that WY14643 (a PPARα agonist) and long-chain fatty acids induce CPT1α gene expression through this site. PPARα plays a key role in lipid metabolism and energy balance by directly regulating the expression of the CPT1α gene and enhancing the fatty acid oxidation process. The activity and expression level of CPT1α are directly affected by PPARα, and the two work together in metabolic regulation to maintain the body's energy homeostasis. By testing the activity of the CPT1α gene, it can be determined that piperidine ring compounds have an agonistic effect on PPARα.

[0166] HepG2 cells are human hepatoma cells cultured in MEM medium containing 1% penicillin / streptomycin and 10% FBS.

[0167] HepG2 cells were plated in 12-well plates at a density of 1.5X105 cells / well in 1 ml of culture medium. After 24 hours, the culture medium was replaced with the compound (10 μM) or DMSO for 24 hours, and total RNA was extracted with Trizol. The 10 μM "compound" refers to LY-sc105, LY-sc208, LY-sc247, LY-sc249, LY-sc262 prepared in the examples of the present application, or commercially available WY14643. Each group used only one of the compounds (the DMSO group did not contain the above compounds).

[0168] Total RNA was extracted with Trizol reagent (Yeasen), reverse transcribed using 5×ABScript III RT Master Mix (Abclonal), and real-time PCR was performed using 2×SYBR Green Fast qPCR Mix (Abclonal). All results were normalized to GAPDH expression (with glyceraldehyde-3-phosphate dehydrogenase as the internal reference 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 effect of LY-sc105, LY-sc208, LY-sc247, LY-sc249, and LY-sc262 on CPT1α. Figure 1 As shown. The biological activity results show that LY-sc247, LY-sc249, and LY-sc262 can enhance CPT1α transcription. It can be reasonably considered that the process is: the piperidine ring compounds of the embodiments of the present application have an agonist effect on the PPARα receptor, and then the expression of the CPT1α gene is regulated by PPARα and the transcription is enhanced. This shows that the piperidine ring compounds or pharmaceutically acceptable salts thereof prepared in the present application have the potential to treat non-alcoholic fatty liver disease, and can be used to prepare drugs for treating non-alcoholic fatty liver disease, such as directly participating as a component of a drug product, or as an intermediate for preparing a drug.

[0170] In the description of this specification, the description with reference to the terms "one embodiment", "certain embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0171] The above is a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the principle of the present invention. These improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A piperidine ring compound, characterized in that, It has the structure shown in structural formula I: Structural formula Ⅰ Wherein, R is C1~C10 substituted or unsubstituted alkyl, C1~C6 substituted or unsubstituted cycloalkyl, C6~C12 substituted or unsubstituted aryl or C4~C6 substituted or unsubstituted heteroaryl; R1 is optionally substituted methoxyphenyl; R2 is H, C1~C6 substituted or unsubstituted alkyl, C1~C6 substituted or unsubstituted cycloalkyl, C6~C12 substituted or unsubstituted aryl or C4~C6 substituted or unsubstituted heteroaryl.

2. The piperidine ring compound according to claim 1, characterized in that R1 is one of the following groups: 。 3. The piperidine ring compound according to claim 1, characterized in that: R2 is one of the following groups: 。 4. The piperidine ring compound according to claim 1, characterized in that: R has the structure shown in structural formula II: Structural formula Ⅱ Wherein, X is a secondary amine 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 an ester group or a carboxyl group-containing group.

5. The piperidine ring compound according to claim 4, characterized in that: R3 is one of the following groups: ； Any end of the above structure is connected to the oxygen atom in structural formula I, and the other end is connected to X.

6. The piperidine ring compound according to claim 4, characterized in that: R4 is one of the following groups: 。 7. A pharmaceutically acceptable salt of the piperidine ring compound according to any one of claims 1 to 6.

8. A method for synthesizing a piperidine ring compound, characterized in that: The following steps are involved: 5-bromopyridin-3-ol is reacted with 4-pyrazoleboronic acid pinacol ester to generate 5-(1H-pyrazol-4-yl)pyridin-3-ol; Using benzyl bromide to attach a benzyl protecting group to the N atom on the pyridine ring of the 5-(1H-pyrazol-4-yl)pyridin-3-ol; Catalytic hydrogenation to obtain 1-benzyl-5-(1H-pyrazol-4-yl)piperidin-3-ol; Reacting 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; reacting with R-4-methylbenzenesulfonate to obtain a compound having a structure of formula III; Structural formula Ⅲ Retaining the benzyl protecting group, or removing the benzyl protecting group and then attaching the R2 group, to obtain the piperidine ring compound having the structure of formula I; Structural formula Ⅰ Wherein, R is C1~C10 substituted or unsubstituted alkyl, C1~C6 substituted or unsubstituted cycloalkyl, C6~C12 substituted or unsubstituted aryl or C4~C6 substituted or unsubstituted heteroaryl; R1 is optionally substituted methoxyphenyl; R2 is H, C1~C6 substituted or unsubstituted alkyl, C1~C6 substituted or unsubstituted cycloalkyl, C6~C12 substituted or unsubstituted aryl or C4~C6 substituted or unsubstituted heteroaryl.

9. Use of the piperidine ring compound according to any one of claims 1 to 6 and the pharmaceutically acceptable salt according to claim 7 in the preparation of a drug for treating non-alcoholic fatty liver disease.

10. A drug for treating non-alcoholic fatty liver disease, characterized in that: It is prepared by using the piperidine ring compound according to any one of claims 1 to 6 or the pharmaceutically acceptable salt according to claim 7.

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