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CN-121974844-A - N-pyridine piperazine compound and preparation method and application thereof

CN121974844ACN 121974844 ACN121974844 ACN 121974844ACN-121974844-A

Abstract

The invention discloses an N-pyridine piperazine compound, a preparation method and application thereof, and belongs to the technical field of chemical pharmacy. The structure of the imidazopyridine compound is shown as a formula I: (I) R is-OH, -H, -OR 1 , OR-NHR 2 , wherein R 1 and R 2 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 8 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl. The novel N-pyridine piperazine compound prepared by the invention has simple and easy preparation process, and pharmacological experiments show that the N-pyridine piperazine compound provided by the invention has USP5 enzymatic inhibition activity and inhibition activity on various tumor cells, is more sensitive to breast cancer cells, has good plasma stability, liver microsome metabolic stability and oral bioavailability, has high-efficiency breast cancer resistance in vivo and in vitro, and is suitable for development of anti-breast cancer drugs.

Inventors

  • ZHANG KUN
  • ZHANG CHENGLIN
  • LI XIANKAI
  • ZHI WUBIN
  • CUI DEYUN
  • QI PENG
  • LIU PENG
  • SONG HENG
  • WANG LIJUN
  • LI JIANJUN
  • ZHANG SHUZHAN
  • WANG PENG

Assignees

  • 河南省科学院化学研究所
  • 河南省科学院

Dates

Publication Date
20260505
Application Date
20260327

Claims (10)

  1. 1. The N-pyridine piperazine compound is characterized in that the structure of the compound is shown as a general formula I: (I), The R is-OH, -H, -OR 1 , OR-NHR 2 , wherein R1 and R 2 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 8 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
  2. 2. The N-pyridinylpiperazine compound according to claim 1, characterized in that R is selected from any one of the following structures: -OEt,-OH, , , , , , , , , , , , , , , , 。
  3. 3. A process for the preparation of an N-pyridinylpiperazine compound according to claim 1 or 2, characterized by comprising the steps of: (1) Dissolving a compound S1, a compound S2, triethylamine and 4-dimethylaminopyridine in dichloromethane, stirring for reaction, washing an organic phase obtained after the reaction is completed, drying, filtering, concentrating and purifying to obtain a compound M1, wherein the structural formula of the compound S1 is The structural formula of the compound S2 is ; (2) Dissolving the compound M1, the compound S3 and the potassium carbonate obtained in the step (1) in DMF, heating and stirring for reaction, cooling, diluting, extracting, washing, drying, filtering, concentrating and purifying to obtain the N-pyridine piperazine compound T1, wherein the structural formula of the compound M1 is The structural formula of the compound S3 is ; (3) Dissolving the N-pyridine piperazine compound T1 and LiOH H 2 O obtained in the step (2) in a solvent, stirring for reaction, performing rotary evaporation after the reaction is completed, and filtering, washing and drying the residue after the pH value is regulated to obtain an N-pyridine piperazine compound T2; (4) Dissolving the N-pyridine piperazine compound T2, the amine compound, the HATU and the DIPEA obtained in the step (3) in DMF, stirring for reaction, diluting after the reaction is complete, extracting, and then washing, drying, filtering, concentrating and purifying to obtain the N-pyridine piperazine compound.
  4. 4. The method according to claim 3, wherein the molar ratio of the compound S1 to the compound S2 to the triethylamine to the 4-dimethylaminopyridine in the step (1) is 1:1-1.5:1.5-3:0.1-0.25, the initial concentration of the compound S1 is 0.15-0.5M, and the stirring time is 8-24 hours.
  5. 5. The method according to claim 4, wherein the molar ratio of the compound M1 to the compound S3 to the potassium carbonate in the step (2) is 1:1-1.5:2-4, the initial concentration of the compound M1 is 0.12-0.2M, the temperature of the heating and stirring is 50-90 ℃ and the time is 8-24h.
  6. 6. The method according to claim 5, wherein the molar ratio of the N-pyridinium piperazine compound T1 to LiOH H 2 O in the step (3) is 1:3-10, the initial concentration of the N-pyridinium piperazine compound T1 is 0.1-0.25M, the solvent is a mixed solvent of methanol and water, the stirring time is 0.5-3H, the pH is adjusted to 3-4 by using a hydrochloric acid solution, and the concentration of the hydrochloric acid solution is 0.5-2M.
  7. 7. The process according to claim 6, wherein the molar ratio of the N-pyridylpiperazine compound T2, the amine compound, the HATU and the DIPEA in the step (4) is 1:1-1.5:1.2-2:1.5-3, the initial concentration of the N-pyridylpiperazine compound T2 is 0.1-0.4M, the amine compound is a substituted or unsubstituted amine selected from the group consisting of a substituted or unsubstituted C3-C8 cycloalkylamine, a substituted or unsubstituted arylamine, a substituted or unsubstituted heteroarylamine, and the stirring time is 6-18h.
  8. 8. The method according to claim 7, wherein the amine compound in the step (4) is selected from any one of cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclic amine, aniline, 4-aminopyridine, 4-nitriloaniline, 4-nitroaniline, 4-methylaniline, 4-fluoroaniline, 4-chloroaniline, 4-bromoaniline, 1-naphthylamine, 4-fluoro-1-naphthylamine, 8-fluoro-1-naphthylamine and 5-fluoro-1-naphthylamine.
  9. 9. Use of an N-pyridinylpiperazine compound according to claims 1-2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting deubiquitinase USP 5.
  10. 10. A pharmaceutical composition comprising the N-pyridinylpiperazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, further comprising at least one pharmaceutically acceptable excipient.

Description

N-pyridine piperazine compound and preparation method and application thereof Technical Field The invention belongs to the technical field of chemical pharmacy, and particularly relates to preparation and application of a USP5 inhibitor compound. Background Ubiquitin-protease system (UPS) is a core mechanism of eukaryotic cells to regulate protein homeostasis, deubiquitinase (Deubiquitinating Enzymes, DUBs) is an important component of the system, and by reversing ubiquitination modification of substrate proteins, target protein stability is maintained and involved in fine regulation of various signaling pathways. About 100 DUBs encoding genes have been identified in the human genome, belonging to USP, UCH, OTU, MJD and JAMM/mpn+five families. The maximum number of USP family members is shown to be abnormally high in various malignant tumors, and the USP family members become important targets for developing anti-tumor medicines. Studies have demonstrated that small molecule inhibitors targeting DUBs such as USP7, UCHL1, etc. exhibit good efficacy in hematological tumors and neurodegenerative diseases, and have entered the clinical trial stage in part. For example, the invention patent publication No. CN105705504A discloses a deubiquitinase inhibitor and a using method thereof, provides a compound capable of inhibiting DUBs and related strategies, can be used for treating pathogenic infection, inhibiting cell proliferation, reducing cell survival rate or inhibiting tumor metastasis, and has application prospects in treatment of neurodegenerative diseases and symptoms thereof. USP5 is a member of the USP family whose expression is broader and is thought to be primarily involved in the cleavage and recycling of free polyubiquitin chains in conventional wisdom. In recent years, more and more studies have revealed that USP5 expression levels are significantly elevated in various solid tumors such as breast cancer, colorectal cancer, glioblastoma, and the like, and are closely related to poor prognosis. For example, the invention patent with publication number CN118203576A discloses a combined anti-tumor application of a USP5 inhibitor and a PD-1 antibody, the YTH structural domain is taken as a key region for ubiquitination modification of YTHDF protein, and the screening is carried out to obtain a deubiquitinase USP5 inhibitor WP1130, which is proved to be capable of negatively regulating the PD-L1 expression level by interfering YTHDF1 protein steady state. While the important role of USP5 in the development of tumorigenesis is increasingly recognized, no inhibitors against USP5 are currently marketed in bulk, nor are drug candidates entering the clinical stage. The prior reported small molecule compounds (such as G9, spautin-1) have the problems of poor metabolic stability, low bioavailability and the like, and severely limit the further application of the small molecule compounds as chemical probes or therapeutic drugs. Therefore, a novel small molecular compound which has good metabolic stability and bioavailability, can efficiently target USP5 and induce tumor cell death is developed, and has important scientific significance and clinical application value. Disclosure of Invention Aiming at the technical problems of poor metabolic stability and low bioavailability of the existing USP5 inhibitor, the invention provides an N-pyridine piperazine compound, and a preparation method and application thereof. In order to achieve the above object, the technical scheme of the present invention is as follows: The invention provides an N-pyridine piperazine compound, the structure of which is shown as a general formula (I): (I), The R is-OH, -H, -OR 1, OR-NHR 2, wherein R1 and R 2 are each independently selected from hydrogen, C 1-C6 alkyl, C 1-C8 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl. Preferably, R is selected from any one of the following structures: The invention provides a preparation method of the N-pyridine piperazine compound, which comprises the following preparation processes: ; The method comprises the following steps: (1) Dissolving a compound S1, a compound S2, triethylamine and 4-dimethylaminopyridine in dichloromethane, stirring for reaction, washing an organic phase obtained after the reaction is completed, drying, filtering, concentrating and purifying to obtain a compound M1, wherein the structural formula of the compound S1 is The structural formula of the compound S2 is; (2) Dissolving the compound M1, the compound S3 and the potassium carbonate obtained in the step (1) in DMF, heating and stirring for reaction, cooling, diluting, extracting, washing, drying, filtering, concentrating and purifying to obtain the N-pyridine piperazine compound T1, wherein the structural formula of the compound M1 isThe structural formula of the compound S3 is; (3) Dissolving the N-pyridine piperazine compound T1 and LiOH H 2 O obtained in the step (2) in a solvent, stirring for reacti