Substituted 1-benzoyl-4-piperidine formamido acetic acid compound and preparation method and pharmaceutical application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a substituted 1-benzoyl-4-piperidine formamido acetic acid compound as well as a preparation method and medicinal application thereof. Specifically, the invention discloses a substituted 1-benzoyl-4-piperidine formamido acetic acid compound as shown in a general formula (I), a physiologically acceptable salt thereof, a preparation method of the compound, application of the compound in preparation of a protein tyrosine phosphatase 1B (PTP1B) inhibitor, a pharmaceutical preparation containing the compound, and a preparation method of the compound. The invention also discloses application of the compound in preparation of drugs for preventing and / or treating PTP1B-related diseases, such as diabetes, obesity and cancer.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to substituted 1-benzoyl-4-piperidinylcarboxamidoacetic acid compounds represented by general formula (I), and physiologically acceptable salts thereof; pharmaceutical compositions and preparation methods of these compounds, and the use of these compounds in the preparation of protein tyrosine phosphatase 1B (PTP1B) inhibitors, and in the preparation of drugs for preventing or treating PTP1B-related diseases. Background Art

[0002] Protein tyrosine phosphatase 1B (PTP1B), a classic non-receptor PTP encoded by the PTPN1 gene, is an important tyrosine dephosphorylase in the body. PTP1B is primarily localized in the endoplasmic reticulum and is present in multiple tissues, including adipocytes, hepatocytes, muscle cells, and epithelial cells. Studies have demonstrated that PTP1B plays a crucial negative regulatory role in the insulin and leptin signaling pathways, and its inhibitors hold promise in the treatment of diabetes and obesity. Furthermore, PTP1B protein expression levels are significantly elevated in cancers such as colorectal, prostate, gastric, ovarian, and particularly breast cancer. Studies have shown that genetic deletion of PTPN1 in tumor or immune cells can promote anti-tumor immunity, enhancing the anti-tumor activity of endogenous T cells and synergizing with blockade of cell surface checkpoints such as PD-1. It can also enhance the efficacy of CAR-T cells. PTP1B inhibitors are currently being used in clinical trials for cancer immunotherapy, providing an alternative therapeutic strategy for combating cancer.

[0003] A number of small-molecule PTP1B inhibitors have been developed, but to date, no PTP1B-targeting drugs have been marketed. Ertiprotafib, Trodusquemine, JTT-551, and ABBV-CLS-484 are the only PTP1B inhibitors that have entered clinical trials. Clinical studies of ertiprotafib, Trodusquemine, and JTT-551 have been terminated due to insufficient efficacy or significant side effects. ABBV-CLS-484 is the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and is currently being evaluated in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT04777994).

[0004] The unsatisfactory action specificity and bioavailability are the main reasons for the poor efficacy or obvious side effects of PTP1B inhibitors. Therefore, it is of important practical significance and application prospect to study new PTP1B inhibitors with high activity, high selectivity and good bioavailability, and explore their use and potential in related diseases. SUMMARY

[0005] The present application aims to provide a substituted 1-benzoyl-4-piperidinecarboxamide acetic acid compound represented by the following general formula (I) and its physiologically acceptable salt, which has good PTP1B inhibitory activity and can be used for treating PTP1B related diseases such as diabetes, obesity, cancer and the like. The technical problem solved by the present application is to provide a substituted 1-benzoyl-4-piperidinecarboxamide acetic acid compound represented by formula (I), a preparation method thereof, a pharmaceutical composition and use in preparing PTP1B inhibitors, and use in preparing a prophylactic or therapeutic agent for PTP1B related diseases.

[0006] In order to solve the technical problem of the present application, the present application adopts the following technical solution:

[0007] The first aspect of the technical solution of the present application is to provide a substituted 1-benzoyl-4-piperidinecarboxamide acetic acid compound represented by the following general formula (I) and its physiologically acceptable salt,

[0008]

[0009] wherein R1 is selected from phenyl, phenoxy, cyclohexyl, halogen; R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indole, cyclohexyl; the substituent is a single or multiple substituent group, which is independently selected from halogen, hydroxyl; n is selected from 0 or 1.

[0010] The preferred compound is a compound represented by the general formula (IA) and its physiologically acceptable salt:

[0011]

[0012] wherein R1 is selected from phenyl, phenoxy, cyclohexyl, halogen; R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indole, cyclohexyl; the substituent is a single or multiple substituent group, which is independently selected from halogen, hydroxyl.

[0013] The preferred compound is a compound represented by the general formula (IB) and its physiologically acceptable salt:

[0014]

[0015]

[0016] Wherein, R2 is selected from substituted or unsubstituted phenyl and cyclohexyl; the substituents are monosubstituted or polysubstituted groups, which are independently selected from halogen and hydroxyl. The most preferred compound is the following compound and its physiologically acceptable salt, characterized in that the compound is selected from:

[0017]

[0018]

[0019]

[0020] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound represented by general formula (I), characterized in that it comprises the following steps:

[0021]

[0022] The starting material substituted aniline reacts with p-anisaldehyde through reductive amination to produce intermediate I-1. p-Bromomethylbenzoic acid reacts with ethyl 4-piperidinic acid to produce intermediate I-2. Intermediates I-1 and I-2 are alkylated with nitrogen to produce I-3, which is then hydrolyzed to produce carboxylic acid intermediate I-4. I-4 is condensed to produce intermediate I-5, which is then hydrolyzed to produce the target compound. R1, R2, and n are as defined in claim 1.

[0023] A third aspect of the present invention provides a pharmaceutical composition comprising an effective dose of any of the substituted 1-benzoyl-4-piperidinylcarboxamidoacetic acid compounds and physiologically acceptable salts thereof described in the first aspect of the present invention, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained-release formulations, controlled-release formulations, and various microparticle delivery systems.

[0024] In order to prepare pharmaceutical preparations, the compound represented by general formula I can be mixed with suitable pharmaceutical carrier substances, fragrances, flavorings and pigments in a known manner and made into tablets or coated tablets, or suspended or dissolved in water or oil with other additives.

[0025] The compounds of the present invention can be administered orally or parenterally. Oral administration may take the form of tablets, capsules, or coatings, while parenteral dosage forms include injections and suppositories. These preparations are prepared according to methods well known to those skilled in the art. Excipients used to prepare tablets, capsules, and coatings are conventional adjuvants, such as starch, gelatin, gum arabic, silica, and polyethylene glycol. Solvents used in liquid dosage forms include water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Preparations containing the compounds of the present invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and pigments.

[0026] The fourth aspect of the present invention provides the use of the substituted 1-benzoyl-4-piperidinylcarboxamidoacetic acid compounds and physiologically acceptable salts thereof described in the first aspect in the preparation of a drug for preventing or treating a PTP1B-related disease selected from diabetes, obesity, and cancer.

[0027] Beneficial technical effects:

[0028] The compounds involved in the present invention have a novel pTyr mimetic structure - 1-benzoyl-4-piperidinylcarboxamidoacetic acid, which has a significant PTP1B inhibitory effect. Among them, most of the compounds have an inhibitory activity of more than 90% on PTP1B at a concentration of 10μM, and the IC 50 The values ​​reached μM level, and the IC values ​​of the four compounds for PTP1B 50 The value was less than 1 μM. DETAILED DESCRIPTION

[0029] The invention will be further described below with reference to the following examples, but these examples do not limit the scope of the invention.

[0030] All reagents and solvents used in the synthesis experiments were purchased from commercial sources and used without further treatment. Anhydrous solvents were commercially available ultra-dry solvents, and the solvent mixing ratios were by volume. All reactions were monitored using GF-254 thin-layer silica gel plates, and column chromatography separations were performed using 200-300 mesh silica gel. 1 H-NMR spectra were acquired on a Varian Mercury 400-MHz NMR spectrometer. Chemical shifts (δ) are given in parts per million (ppm) with TMS as the internal standard, and coupling constants are in Hertz (Hz).

[0031] Example 1: Preparation of TM-1

[0032]

[0033] (1) Preparation of intermediate I-1

[0034]

[0035] 4-Aminodiphenyl ether (5.56 g, 30 mmol) and p-anisaldehyde (2.43 mL, 20 mmol) were dissolved in 50 mL of anhydrous methanol. Two drops of glacial acetic acid were added dropwise, followed by the addition of 1% molecular sieves. The mixture was heated under reflux at 80°C for approximately 6 h. After TLC analysis, the reaction solution was cooled to room temperature and sodium cyanoborohydride (1.25 g, 20 mmol) was gradually added. After reacting at room temperature for half an hour, the mixture was heated at 40°C for approximately 1 h. TLC analysis confirmed the reaction was complete. The reaction solution was quenched with water, extracted three times with ethyl acetate, and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure, and separated by column chromatography (petroleum ether:ethyl acetate 5:1) to afford 3.94 g of intermediate I-1 in a 65% yield. 1 H NMR (400MHz, DMSO-d6) δ7.35-7.27(m,4H),7.01(t,J=7.4Hz,1H),6.92(d,J=8.9Hz,2H),6.84(d ,J=8.2Hz,4H),6.63(d,J=8.9Hz,2H),6.12(t,J=5.9Hz,1H),4.19(d,J=5.9Hz,2H),3.75(s,3H).

[0036] (2) Preparation of intermediate I-2

[0037]

[0038] p-Anisic acid (1.07 g, 5 mmol) was dissolved in 30 mL of anhydrous dichloromethane. Oxalyl chloride (0.86 mL, 10 mmol) was added dropwise in an ice bath. Two drops of N,N-dimethylformamide were also added dropwise. The mixture was stirred at room temperature until dissolved. The reaction was completed as monitored by TLC. Most of the solvent was removed under reduced pressure. 20 mL of anhydrous tetrahydrofuran was added and stirring in the ice bath was continued. In a flask, ethyl 4-piperidinate (0.77 mL, 5 mmol), triethylamine (1.39 mL, 10 mmol) and 20 mL of anhydrous tetrahydrofuran were added dropwise to the reaction solution. After about 1 h, the reaction was completed as monitored by TLC. Most of the solvent was removed under reduced pressure. Water was added and the mixture was extracted three times with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain intermediate I-2, 1.20 g, in a yield of 70%. 1H NMR (400MHz, DMSO-d6) δ7.50(d,J=7.7Hz,2H),7.39(d,J=7.7Hz,2H),4.80(s,2H),4.32(s,1H),4.08(q,J=7.1Hz,2H),3.52(s ,1H),3.08(s,1H),2.96(s,1H),2.63(t,J=11.0,1H),1.90(s,1H),1.80(s,1H),1.52(d,J=11.0Hz,2H),1.18(t,J=7.1Hz,3H).

[0039] (3) Preparation of intermediate I-3

[0040]

[0041] Intermediate I-1 (1.51 g, 5 mmol), potassium carbonate (1.10 g, 8 mmol), and intermediate I-2 (2.65 g, 7.5 mmol) were added to 25 mL of N,N-dimethylformamide, and the reaction system was heated to 65°C for 8 h. The reaction was monitored for completion by TLC. Most of the solvent was removed under reduced pressure, and water was added. The product was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated by column chromatography (petroleum ether:ethyl acetate 6:1) to afford intermediate I-3 (2.15 g, 75% yield). 1 H NMR (400MHz, DMSO-d6) δ7.52(d,J=7.8Hz,1H),7.41(d,J=8.2Hz,1H),7.38-7.31(m,4H),7.29(d,J=7.8 Hz,1H),7.21(d,J=8.2Hz,2H),7.01(t,J=7.3Hz,1H),6.92(s,1H),6.89(d,J=7.3Hz,2H),6.85(d,J=8. 6Hz,3H),6.73(d,J=8.6Hz,2H),4.68(s,2H),4.61(s,2H),4.35(s,1H),4.09(d,J=7.1,2H),3.74(s,3H ),3.55(s,1H),3.38(s,1H),3.02(s,3H),2.52(s,1H),1.85(s,2H),1.53(s,3H),1.20(t,J=7.1Hz,4H).

[0042] (4) Preparation of intermediate I-4

[0043]

[0044] Intermediate I-3 (1.15 g, 22 mmol) and lithium hydroxide (252 mg, 6 mmol) were added to 30 mL of a 3:1:1 mixture of tetrahydrofuran, methanol, and water and stirred at room temperature for 6 h. Following completion of the reaction, as monitored by TLC, the majority of the solvent was removed under reduced pressure. The mixture was then diluted with water and the pH slowly adjusted to 4-5 with 1N aqueous hydrochloric acid. The precipitated solid was filtered to afford 0.98 g of Intermediate I-4 as a white solid in a 90% yield. 1 H NMR (400MHz, DMSO-d6) δ7.38-7.33(m,4H),7.31(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.02(t,J=7.4Hz,1H),6.91(d,J=8.0Hz,2H),6.87(d ,J=8.7,4H),6.73(d,J=8.7Hz,2H),4.70(s,2H),4.63(s,2H),4.29(s, 1H),3.75(s,3H),3.56(s,1H),3.07(s,2H),1.83(s,2H),1.51(s,2H).

[0045] (5) Preparation of intermediate I-5

[0046]

[0047] Intermediate I-4 (574 mg, 1 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 456 mg, 1.2 mmol), and N,N-diisopropylethylamine (DIPEA, 346 μL, 3 mmol) were added to 10 mL of N,N-dimethylformamide and stirred at room temperature for 0.5 h. Following completion of the reaction by TLC, DL-phenylalanine methyl ester hydrochloride (215 mg, 1 mmol) was added and stirred at room temperature for 8 h. The reaction solution was added with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate 1:1) to afford 611 mg of intermediate I-5 in an 86% yield. 1H NMR (400MHz, DMSO-d6) δ8.29(d,J=7.9Hz,1H),7.31(s,4H),7.27(dd,J=10.7,7.9Hz,4H),7.23-7.18( m,5H),7.00(t,J=7.9Hz,1H),6.89(d,J=8.6Hz,2H),6.85(dd,J=8.6,3.3Hz,4H),6.71(d,J=8.6Hz,2H ),4.67(s,2H),4.61(s,2H),4.52-4.43(m,1H),4.32(s,2H),3.72(s,3H),3.60(s,3H),3.04(dd,J=13 .7,7.9Hz,1H),2.88(dd,J=13.7,7.9Hz,1H),2.46-2.38(m,1H),1.66-1.30(m,5H),0.89-0.80(m,1H).

[0048] (6) Preparation of target compound TM-1

[0049]

[0050] The synthesis method is similar to that of intermediate I-4, except that I-5 is used instead of I-3, to obtain 110 mg of a white solid with a yield of 87%. 1 H NMR (400MHz, DMSO-d6) δ12.56 (s, 1H), δ8.12 (d, J = 8.2Hz, 1H), 7.34 (s, 4H), 7.29 (d, J = 7.4Hz, 4H), 7. 25-7.19(m,5H),7.02(t,J=7.4Hz,1H),6.92(d,J=8.2Hz,2H),6.87(d,J=8.2Hz,4H),6.73(d,J=8.2Hz ,2H),4.69(s,2H),4.63(s,2H),4.51-4.42(m,1H),4.40(s,1H),3.74(s,3H),3.56(s,1H),3.09(d,J =13.8Hz,1H),3.00(s,1H),2.87(d,J=13.8Hz,1H),2.69(s,1H),2.48-2.37(m,1H),1.87-1.22(m,4H)

[0051] Example 2: Preparation of TM-2

[0052]

[0053] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by L-phenylalanine methyl ester hydrochloride to obtain 71 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.66 (s, 1H), δ8.13 (d, J = 8.3Hz, 1H), 7.31 (s, 4H), 7.28 (d, J = 7.3Hz, 2H), 7.25 (d, J = 7.3Hz, 2H) ,7.23-7.16(m,5H),7.00(t,J=7.3Hz,1H),6.89(d,J=8.3Hz,2H),6.83-6.67(m,2H),6.83(d,J=4.6Hz,2H),6.71(d,J=8. 9Hz,2H),4.67(s,2H),4.60(s,2H),4.42(t,J=7.3Hz,1H),3.72(s,3H),3.54(s,1H),3.07(dd,J=13.6,4.6Hz,1H),2.97( s,1H),2.84(dd,J=13.6,10.1Hz,1H),2.67(s,1H),2.56(s,1H),2.40(d,J=10.1Hz,1H),1.58(s,1H),1.52-1.06(m,3H).

[0054] Example 3: Preparation of TM-3

[0055]

[0056] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by D-phenylalanine methyl ester hydrochloride to obtain 45 mg of a white solid. 1 H NMR(400MHz,MeOD)δ7.39(q,J=7.5Hz,4H),7.34-7.18(m,9H),7.02(t,J=7.5 Hz,1H),6.90(d,J=8.5Hz,4H),6.83(q,J=8.5Hz,4H),4.71(s,1H),4.67(s,2 H),4.62(s,2H),4.51(s,1H),3.81(s,3H),3.70(s,1H),3.28(s,1H),3.10(s ,1H),3.04-2.87(m,2H),2.53(s,1H),1.94-1.61(m,2H),1.61-1.28(m,2H).

[0057] Example 4: Preparation of TM-4

[0058]

[0059] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-3-(2-naphthyl)alanine to obtain 53 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.83(s,1H),7.79(d,J=8.1Hz,2H),7.67(s,1H),7.42(s,1H),7.38(d,J =8.5Hz,2H),7.33-7.27(m,5H),7.26(s,1H),7.20(d,J=8.1Hz,2H),7.00(t,J=8.1Hz,1H),6.89(d,J=8.5Hz, 2H),6.85(d,J=8.5Hz,4H),6.71(d,J=8.5Hz,2H),4.67(s,2H),4.61(s,2H),4.50-4.42(m,1H),4.28(s,1H), 3.72(s,3H),3.22-3.27(m,2H),3.10-2.99(m,1H),2.84(s,2H),2.41(s,1H),1.56(s,1H),1.51-1.17(m,3H).

[0060] Example 5: Preparation of TM-5

[0061]

[0062] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-tryptophan ethyl ester hydrochloride to obtain 55 mg of a white solid. 1H NMR (400MHz, DMSO-d6) δ12.62(s,1H), δ10.80(s,1H),8.06(d,J=7.9Hz,1H),7.52(d,J=7.9Hz,1H),7.31(s,5H),7.28 (d,J=7.9Hz,2H),7.20(d,J=8.6Hz,2H),7.11(s,1H),7.00(t,J=7.9Hz,3H),6.89(d,J=8.6Hz,2H),6.85(d,J=8.6Hz,4 H),6.71(d,J=8.6Hz,2H),4.67(s,2H),4.61(s,2H),4.49-4.41(m,1H),3.72(s,3H),3.54(s,1H),3.17(d,J=14.6Hz, 1H), 3.00 (d, J = 14.6Hz, 1H), 2.82 (s, 1H), 2.67 (s, 1H), 2.58 (s, 1H) 2.46-2.39 (m, 1H), 1.60 (s, 1H), 1.53-1.31 (m, 3H).

[0063] Example 6: Preparation of TM-6

[0064]

[0065] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-tyrosine methyl ester hydrochloride to obtain 48 mg of a white solid. 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.31(s,4H),7.28(d,J=7.9Hz,2H),7.19(d,J=8.6Hz,2H),7 .00(t,J=7.9Hz,1H),6.89(d,J=8.1Hz,4H),6.84(d,J=8.6Hz,4H),6.71(d,J=8.6Hz,2H),6.56(d, J=7.9Hz,2H),4.67(s,2H),4.60(s,2H),4.35(s,1H),4.00(s,1H),3.72(s,3H),3.54(s,1H),3.09 -2.90(m,2H),2.73-2.80(m,1H),2.67(s,1H),2.45-2.32(m,1H),1.56(s,1H),1.52-1.28(m,2H).

[0066] Example 7: Preparation of TM-7

[0067]

[0068] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-fluorophenylalanine hydrochloride to obtain 58 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.70(s,1H),7.32(s,4H),7.28(d,J=8.2Hz,2H),7.20(d,J=8.8Hz,4H) ,7.03(d,J=8.2Hz,3H),6.89(d,J=8.2Hz,2H),6.85(dd,J=8.2Hz,4H),6.71(d,J=8.8Hz,2H),4 .67(s,2H),4.61(s,2H),4.20(s,1H),3.72(s,3H),3.51(s,1H),3.06(d,J=13.3Hz,1H),3.00( s,1H),2.86(dd,J=13.3,8.2Hz,1H),2.41(s,1H),1.58(s,1H),1.52-1.30(m,3H),1.23(s,2H).

[0069] Example 8: Preparation of TM-8

[0070]

[0071] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-chlorophenylalanine hydrochloride to obtain 61 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.15(d,J=8.2Hz,1H),7.32(s,6H),7.28(d,J=7.6Hz,2H),7.21(d,J=8.2Hz,4H), 7.00(t,J=7.6Hz,1H),6.89(d,J=8.2Hz,2H),6.85(dd,J=8.6,4.5Hz,4H),6.71(d,J=8.6Hz,2H),4.68(s,2 H),4.61(s,2H),4.42(td,J=10.0,4.5Hz,1H),4.34(s,1H),3.72(s,3H),3.06(dd,J=13.8,4.5Hz,1H),2. 98(s,1H),2.84(dd,J=13.8,10.0Hz,2H),2.67(s,1H),2.46-2.36(m,1H),1.60(s,2H),1.47-1.21(m,2H).

[0072] Example 9: Preparation of TM-9

[0073]

[0074] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-bromophenylalanine hydrochloride to obtain 47 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.0Hz,1H),7.43(d,J=8.0Hz,2H),7.32(s,4H),7.28(d,J=8.5Hz,2H),7.20( d,J=8.5Hz,2H),7.15(d,J=8.0Hz,2H),7.00(t,J=7.3Hz,1H),6.89(d,J=8.5Hz,2H),6.84(dd,J=8.5,4.2Hz,4H) ,6.71(d,J=8.5Hz,2H),4.67(s,2H),4.61(s,2H),4.39-4.30(m,1H),3.72(s,3H),3.54(s,1H),3.05(dd,J=13. 7,4.7Hz,1H),2.97(s,1H),2.83(dd,J=13.7,9.3Hz,2H),2.39(d,J=9.3Hz,1H),1.59(s,2H),1.50-1.18(m,3H).

[0075] Example 10: Preparation of TM-10

[0076]

[0077] The synthesis method is similar to that of TM-1, except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-fluorophenylglycine methyl ester hydrochloride to obtain 39 mg of a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.62(s,1H),7.46(s,2H),7.34(s,5H),7.23(s,4H),7.04(s,2H),6.89(s,5H),6.74(s,3H), 5.36(s,1H),4.69(s,2H),4.66(s,2H),4.47(s,2H),3.77(s,3H),3.03(s,1H),2.85(s,1H),2.63(s,1H),1.74(s,3H),1.51(s,1H).

[0078] Example 11: Preparation of TM-11

[0079]

[0080] The synthesis procedure is similar to TM-1 except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-chlorophenylglycine methyl ester hydrochloride to give 48 mg of white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.40 (s, 5H), 7.32 (s, 5H), 7.18 (s, 2H), 7.00 (s, 1H), 6.94-6.79 (m, 6H), 6.72 (s, 2H), 5.26 (s, 1H), 4.67 (s, 2H), 4.60 (s, 2H), 4.43 (s, 1H), 3.72 (s, 3H), 3.60 (s, 1H), 3.12-2.70 (m, 3H), 1.72 (s, 2H), 1.48 (s, 2H).

[0081] Example 12: Preparation of TM-12

[0082]

[0083] The synthesis procedure is similar to TM-1 except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-chlorophenylglycine methyl ester hydrochloride to give 48 mg of white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.40 (s, 5H), 7.32 (s, 5H), 7.18 (s, 2H), 7.00 (s, 1H), 6.94-6.79 (m, 6H), 6.72 (s, 2H), 5.26 (s, 1H), 4.67 (s, 2H), 4.60 (s, 2H), 4.43 (s, 1H), 3.72 (s, 3H), 3.60 (s, 1H), 3.12-2.70 (m, 3H), 1.72 (s, 2H), 1.48 (s, 2H).

[0084] Example 13: Preparation of TM-13

[0085]

[0086] The synthesis procedure is similar to TM-1 except that DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-chlorophenylglycine methyl ester hydrochloride to give 48 mg of white solid. 1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.35(s,4H),7.31(d,J=8.1Hz,2H),7.22(d,J =8.0Hz,2H),7.03(s,1H),6.91(d,J=8.1Hz,2H),6.87(s,4H),6.74(d,J=8.0Hz,2H ),4.70(s,2H),4.63(s,2H),4.44(s,1H),4.11(s,1H),3.75(s,3H),3.02(s,1H),2 .81(s,1H),2.60(s,1H),1.70(s,5H),1.59(s,4H),1.51(s,1H),1.29-0.97(m,6H).

[0087] Example 14: Preparation of TM-14

[0088]

[0089] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-aminobiphenyl to obtain 55 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.54(d,J=7.6Hz,2H),7.44(d,J=8.4Hz,2H),7.37(t,J=7.6Hz,3H),7. 33(s,4H),7.25-7.19(m,4H),7.19-7.12(m,4H),6.91(d,J=8.2Hz,2H),6.77(d,J=8.4Hz,2H), 4.76(s,2H),4.69(s,2H),4.34(s,1H),4.23-4.12(m,1H),3.74(s,3H),3.55(s,1H),3.12(d,J =9.4Hz,1H),2.90(dd,J=13.5,7.3Hz,2H),2.78(s,1H),2.46-2.35(m,1H),1.74-1.28(m,4H).

[0090] Example 15: Preparation of TM-15

[0091]

[0092] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-aminobiphenyl, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-tryptophan ethyl ester hydrochloride to obtain 58 mg of a white solid. 1HNMR (400MHz, DMSO-d6) δ10.66(s,1H),7.52(d,J=7.7Hz,2H),7.47(d,J=7.9Hz,1H),7.42(d,J=8.4Hz,2H),7.35(t,J=7.7Hz,3H),7 .30(s,4H),7.24(d,J=7.9Hz,1H),7.20(dd,J=7.9,5.3Hz,3H),7.03(s,1H),6.95(d,J=8.6Hz,1H),6.89(d,J=8.6Hz,2H),6.86(d,J =7.4Hz,1H),6.75(d,J=8.4Hz,2H),4.74(s,2H),4.67(s,2H),4.32(s,1H),4.15(s,1H),3.72(s,3H),3.53(s,1H),3.24(dd,J=14.3 ,5.3Hz,1H),3.00(dd,J=14.3,5.3Hz,1H),2.91(s,1H),2.78-2.59(m,1H),2.41-2.29(m,1H),1.77-1.45(m,2H),1.45-1.24(m,2H).

[0093] Example 16: Preparation of TM-16

[0094]

[0095] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-bromoaniline to obtain 57 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.28(q,J=8.0Hz,5H),7.21(d,J=8.5Hz,2H),7.15(d,J=8.3Hz,4H),7 .10(d,J=8.0Hz,3H),6.88(d,J=8.3Hz,2H),6.61(d,J=8.5Hz,2H),4.69(s,2H),4.62(s,2H),4 .33(s,1H),4.04(s,1H),3.71(s,3H),3.53(s,1H),3.09(dd,J=13.3,6.3Hz,1H),2.99(s,1H), 2.90(dd,J=13.3,6.3Hz,1H),2.77(s,1H),2.33-2.39(m,1H),1.56(s,2H),1.51-1.16(m,2H).

[0096] Example 17: Preparation of TM-17

[0097]

[0098] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-bromoaniline, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-3-(2-naphthyl)alanine to obtain 68 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.16(d,J=8.2Hz,1H),7.87-7.83(m,1H),7.81(d,J=8.5Hz,2H),7.70(s,1H ),7.43(s,2H),7.41-7.36(m,1H),7.26(s,4H),7.22(d,J=8.5Hz,2H),7.16(d,J=8.2Hz,2H),6.88(d,J=8.5Hz,2H ),6.62(d,J=8.5Hz,2H),4.69(s,2H),4.63(s,2H),4.57-4.49(m,1H),4.28(s,1H),3.71(s,3H),3.53(s,1H),3.2 5(d,J=13.7Hz,1H),3.03(d,J=13.7Hz,1H),2.90(s,2H),2.37-2.43(m,1H),1.75-1.36(m,3H),1.34-1.15(m,1H).

[0099] Example 18: Preparation of TM-18

[0100]

[0101] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-bromoaniline, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-tryptophan ethyl ester hydrochloride to obtain 79 mg of a white solid. 1H NMR (400MHz, DMSO-d6) δ10.67(s,1H),7.47(d,J=7.9Hz,1H),7.29(s,1H),7.26(s,4H),7.24(s,1H),7.21(d,J=8.6 Hz,2H),7.15(d,J=8.2Hz,2H),7.03(s,1H),6.97(t,J=7.9Hz,1H),6.88(d,J=8.2Hz,2H),6.85(s,1H),6.61(d,J=8. 6Hz,2H),4.68(s,2H),4.62(s,2H),4.31(s,1H),4.14(s,1H),3.71(s,3H),3.53(s,1H),3.25(dd,J=14.3,6.3Hz,1H ),3.00(dd,J=14.3,6.3Hz,1H),2.90(s,1H),2.78-2.62(m,1H),2.34(s,1H),1.76-1.43(m,2H),1.42-1.17(m,2H).

[0102] Example 19: Preparation of TM-19

[0103]

[0104] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-bromoaniline, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-tyrosine methyl ester hydrochloride to obtain 71 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.73(s,1H),9.20(s,1H),8.00(d,J=8.1Hz,1H),7.31(q,J=8.1Hz ,4H),7.23(d,J=8.1Hz,2H),7.18(d,J=8.1Hz,2H),7.00(d,J=8.0Hz,2H),6.90(d,J=8.1Hz, 2H),6.64(t,J=6.9Hz,4H),4.71(s,2H),4.64(s,2H),4.47-4.26(m,2H),3.73(s,3H),3.56 (s,1H),3.11-2.92(m,2H),2.87-2.68(m,2H),2.44(s,1H),1.61(s,2H),1.53-1.30(m,2H).

[0105] Example 20: Preparation of TM-20

[0106]

[0107] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by p-bromoaniline, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-4-chlorophenylalanine hydrochloride to obtain 77 mg of a white solid. 1 HNMR(400MHz,DMSO-d6)δ8.09(d,J=8.3Hz,1H),7.31(q,J=8.3Hz,6H),7.26-7.21(m,4H),7 .18(d,J=8.3Hz,2H),6.90(d,J=8.7Hz,2H),6.64(d,J=8.7Hz,2H),4.72(s,2H),4.64(s,2H) ,4.47-4.27(m,2H),3.74(s,3H),3.55(s,1H),3.08(dd,J=13.7,6.7Hz,1H),3.01(s,1H),2. 87(dd,J=13.7,6.7Hz,1H),2.69(s,1H),2.47-2.38(m,1H),1.60(s,2H),1.51-1.28(m,2H).

[0108] Example 21: Preparation of TM-21

[0109]

[0110] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by 4-cyclohexylaniline to obtain 41 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.29 (s, 3H), 7.15 (d, J = 7.7Hz, 4H), 7.07 (t, J = 7.7Hz, 4H), 6.93 (d, J = 8.3Hz, 2H) ,6.87(d,J=8.3Hz,2H),6.59(d,J=8.3Hz,2H),4.64(s,2H),4.58(s,2H),3.91-3.85(m,1H),3.75(s,1H), 3.71(s,3H),3.05(dd,J=12.8,6.5Hz,1H),2.96(s,1H),2.92(dd,J=12.8,6.5Hz,1H),2.78(s,1H),2.55 (s,1H),2.43-2.24(m,2H),1.72(s,5H),1.64(s,1H),1.57(s,1H),1.48-1.24(m,6H),1.24-1.09(m,1H).

[0111] Example 22: Preparation of TM-22

[0112]

[0113] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by 4-cyclohexylaniline, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by L-phenylalanine methyl ester hydrochloride to obtain 57 mg of a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.29 (s, 3H), 7.16 (t, J = 8.5Hz, 4H), 7.08 (q, J = 7.6Hz, 4H), 6.93 (d, J = 8. 2Hz,2H),6.87(d,J=8.2Hz,2H),6.59(d,J=8.2Hz,2H),4.64(s,2H),4.58(s,2H),3.95-3.87(m,1 H),3.71(s,3H),3.54(s,1H),3.06(dd,J=13.1,5.2Hz,1H),2.98(s,1H),2.91(dd,J=13.1,5.5H z,1H),2.78(s,1H),2.40-2.26(m,2H),1.81-1.62(m,6H),1.62-1.34(m,3H),1.36-1.09(m,6H).

[0114] Example 23: Preparation of TM-23

[0115]

[0116] The synthesis method is similar to that of TM-1, except that 4-aminodiphenyl ether in the first step is replaced by 4-cyclohexylaniline, and DL-phenylalanine methyl ester hydrochloride in the fifth step is replaced by DL-tryptophan ethyl ester hydrochloride to obtain 48 mg of a white solid. 1HNMR (400MHz, DMSO-d6) δ10.61(s,1H),7.46(d,J=8.2Hz,1H),7.28(s,4H),7.23(d,J=8.1Hz,1H),7.17(d,J=8.1H z,2H),7.13(d,J=6.5Hz,1H),6.97(s,1H),6.93(d,J=8.2Hz,2H),6.87(d,J=8.2Hz,3H),6.59(d,J=8.2Hz,2H),4.6 4(s,2H),4.58(s,2H),3.96(d,J=5.8Hz,1H),3.71(s,3H),3.50(s,1H),3.21(d,J=12.9Hz,1H),3.00(dd,J=12.9,5 .8Hz,1H),2.94(s,1H),2.82-2.59(m,1H),2.31(s,2H),1.80-1.62(m,6H),1.55(s,1H),1.29(s,7H),1.17(s,1H).

[0117] Pharmacological experiments:

[0118] Experimental Example 1: In vitro inhibitory activity of target compounds on hURAT1

[0119] method:

[0120] Using p-nitrophenol phosphate (pNPP) as a substrate, human recombinant PTP1B was used to determine the inhibitory activity of the test compound against the enzyme. The test compound and the enzyme were pre-incubated at room temperature for 5 minutes, and the pNPP hydrolysis reaction catalyzed by PTP1B was measured in a 100 μL reaction system. Each reaction solution contained 50 mmol·L -1 HEPES, 5mmol·L -1 DTT, 150mmol·L -1 NaCl, 2mmol·L -1 EDTA and 2mmol·L -1 pNPP, pH 7.0; incubate at 30°C for 10 min; add 50 μL 3 mol·L -1 The enzyme reaction is terminated by adding sodium hydroxide solution. The hydrolysis product sodium p-nitrophenolate has strong light absorption at 405nm. The absorption OD value is measured to calculate the inhibitory effect of the test sample on enzymatic hydrolysis. The system without enzyme is used as a blank control, and the IC value of the compound is calculated by nonlinear regression method. 50 value.

[0121] result:

[0122] The inhibition rates of the above compounds on PTP1B at a concentration of 10 μM were determined respectively; the IC values ​​of the compounds with better inhibitory activity were determined and calculated. 50 The results are shown in Table 1.

[0123] Table 1. Inhibition rate and IC of target compounds against recombinant human PTP1B enzyme 50 value

[0124]

[0125]

Claims

1. A substituted 1-benzoyl-4-piperidinylcarboxamidoacetic acid compound represented by the following general formula (I) and a physiologically acceptable salt thereof: in, R1 is selected from phenyl, phenoxy, cyclohexyl, halogen; R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, and cyclohexyl; the substituent is a monosubstituted or polysubstituted group independently selected from halogen and hydroxyl; n is selected from 0 or 1.

2. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is a compound represented by general formula (IA) and a physiologically acceptable salt thereof: in, R1 is selected from phenyl, phenoxy, cyclohexyl, halogen; R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted indolyl, and cyclohexyl; the substituents are monosubstituted or polysubstituted groups, which are independently selected from halogen and hydroxyl.

3. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IB) and a physiologically acceptable salt thereof: in, R2 is selected from substituted or unsubstituted phenyl and cyclohexyl; the substituent is a monosubstituted or polysubstituted group, which is independently selected from halogen and hydroxyl.

4. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is selected from:

5. The method for preparing the compound according to claims 1 to 4, characterized in that: The following steps are involved: The raw material substituted aniline reacts with p-anisaldehyde through reductive amination to obtain intermediate I-1, p-bromomethylbenzoic acid reacts with ethyl 4-piperidinic acid ester to produce intermediate I-2, intermediates I-1 and I-2 are alkylated with nitrogen to obtain I-3, which is then hydrolyzed to obtain carboxylic acid intermediate I-4, and I-4 is condensed to obtain intermediate I-5, which is then hydrolyzed to obtain the target compound; The definitions of R1, R2, and n are the same as those in claim 1.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition contains an effective dose of any one of the compounds according to any one of claims 1 to 4 and a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle delivery systems.

8. Use of the compound according to any one of claims 1 to 4 and a physiologically acceptable salt thereof in the preparation of a protein tyrosine phosphatase 1B inhibitor.

9. Use of the compound according to any one of claims 1 to 4 and a physiologically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases related to protein tyrosine phosphatase 1B.

10. Use according to claim 9, characterized in that The protein tyrosine phosphatase 1B-related diseases include diabetes, obesity, and cancer.

Images