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CN-121991031-A - (4- (6-Methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound and preparation method and application thereof

CN121991031ACN 121991031 ACN121991031 ACN 121991031ACN-121991031-A

Abstract

The invention discloses a (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound, a preparation method, a pharmaceutical composition and application thereof. The (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound can be specifically combined with the B3GAT3 protein, so that the antitumor effect is exerted, and the compound can be used for treating various tumors. The structural general formula of the compound is shown as (I), and the compound also comprises pharmaceutically acceptable salts thereof, and in addition, the preparation method disclosed by the invention is mature, simple and convenient and has higher yield. (I)。

Inventors

  • YANG YONG
  • ZHANG MENGHAN
  • ZHANG DAYONG
  • Dai Beiying
  • YIN HAO
  • ZHOU WANG
  • WANG ZHI

Assignees

  • 中国药科大学

Dates

Publication Date
20260508
Application Date
20260128

Claims (10)

  1. 1. (4- (6-Methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compounds and pharmaceutically acceptable salts thereof, and are characterized in that the structural general formula of the (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compounds is shown as formula (1): (I) Wherein: The A ring is selected from 5-6 membered heterocycle, 4-6 membered saturated or unsaturated bicyclic heterocycle, 4-6 membered saturated or unsaturated spiro or bridged ring, 2-8 alkane or alkoxy straight chain containing ether, wherein two ends of the 5-6 membered heterocycle are connected by N atoms; R 1 is selected from substituted or unsubstituted C 6 ~ C 12 aryl, 5-10 membered aromatic heterocycle containing 1-2 nitrogen, oxygen and/or sulfur heteroatoms, substituted or unsubstituted benzo 5-6 membered heterocycle, wherein the substituent of the aromatic group of R 1 is mono-substituted or multi-substituted, and the substituent is halogen group, methyl, methoxy or trifluoromethyl; R 2 is selected from 5-position indolyl ester substituted by R 3 or 5-position indolyl ether substituted by R 4 , R 3 is selected from methyl or ethyl; R 4 is selected from the group consisting of C 4 ~ C 8 linear alkyl, C 4 ~ C 8 linear or linear and cyclic alkoxy containing N and/or O hetero atoms, C 4 ~ C 8 ester group, and substituted or unsubstituted C 6 ~ C 10 aromatic group, wherein the substituent is selected from the group consisting of hydrogen atoms.
  2. 2. (4- (6-Methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compounds and pharmaceutically acceptable salts thereof according to claim 1, wherein ring a is selected from any one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 ; r 1 is selected from any one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ; R 2 is selected from any one of the following structures: 、 ; r 3 is selected from methyl or ethyl; r 4 is selected from any one of the following structures: 、 、 、 、 、 、 。
  3. 3. (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compounds and pharmaceutically acceptable salts thereof according to claim 2, wherein the (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compounds are selected from any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。
  4. 4. (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compounds and pharmaceutically acceptable salts thereof according to claim 1, wherein the pharmaceutically acceptable salts are salts of the compounds with any one acid or base selected from the group consisting of: The acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid, and the base is a base containing alkali metal cations, alkaline earth metal cations or ammonium cation salts.
  5. 5. A process for the preparation of (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compounds and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, characterized in that they are synthesized according to the following route: Wherein, the Reflux reaction of 5-methoxyl isatin (1 a) and 2a in alkaline ethanol solution, and acidification after the reaction is finished to obtain a compound 3a; Step two, carrying out acid-amine condensation reaction on the compound 3a and amino with Boc which is substituted differently to obtain a compound 4a; Step three, removing Boc groups from the compound 4a under the action of trifluoroacetic acid and alkalizing to obtain a compound 5a; Step four, the compound 1b reacts with oxalyl chloride in diethyl ether to obtain a compound 2b; step five, the compound 2b reacts with the compound 5a in basic DCM at room temperature to obtain the compound 3b.
  6. 6. A pharmaceutical composition comprising a (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or adjuvant.
  7. 7. A B3GAT3 inhibitor comprising a (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts thereof.
  8. 8. Use of (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-dione compounds and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 6, or a B3GAT3 inhibitor according to claim 7, for the preparation of a medicament for the treatment and/or prevention of diseases associated with B3GAT3 inhibition.
  9. 9. The use according to claim 8, wherein the disease associated with B3GAT3 inhibition is a disorder associated with malignancy, skeletal dysplasia with inappropriate stature, kyphosis, scoliosis and long bone deformities, distal phalangeal and facial deformities, embryonic dysplasia, abnormal cell metabolism and/or differentiation.
  10. 10. The use according to claim 9, wherein the malignancy is liver cancer, lung cancer, pancreatic cancer, gastric cancer, prostate cancer, colorectal cancer, glioma, breast cancer, intrahepatic cholangiocarcinoma, adrenocortical carcinoma, cervical cancer and/or leukemia.

Description

(4- (6-Methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound and preparation method and application thereof Technical Field The invention relates to a (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound, a preparation method thereof, a pharmaceutical composition and application thereof, in particular to a (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound capable of targeting B3GAT3 protein, a preparation method thereof, a pharmaceutical composition and application thereof. Background Hepatocellular carcinoma (hepatocellular carcinoma, HCC) accounts for 85% -90% of primary liver cancer, and its biological behavior is characterized by high malignancy, early-stage spread, significant heterogeneity, and five-year survival rate of less than 20%. In recent years, with the deep resolution of the 'tumor-microenvironment' interaction network and key signal nodes, systemic therapy has gradually shifted from traditional cytotoxic drugs to the molecular targeting era. The multi-kinase inhibitors sorafenib, lenvatinib, by simultaneously blocking angiogenesis-related receptors such as VEGFR, PDGFR and FGFR, can extend the median overall survival (median overall survival, mOS) in advanced patients to about 12-13 months, and are considered as first line standard regimens. However, the dose-limiting toxicity of acquired drug resistance, hand and foot skin reaction, hypertension and the like leads to objective remission rate of less than 10%, and clinical benefit stage is difficult to break through. In addition, HCC presents significant heterogeneity at genomic, epigenetic and proteomic levels, limiting single-target drug efficacy, while biomarker loss, trial endpoint misselection, and patient stratification strategy defects further amplify phase III clinical failure rates. Therefore, finding new tamper-able targets and constructing accurate therapeutic systems based on molecular typing have become urgent issues in current research. Proteoglycans (proteoglycans, PGs) are a class of anionic macromolecules formed by covalent coupling of core proteins with glycosaminoglycans (glycosaminoglycans, GAGs), widely anchored to cell membranes and extracellular matrices, and can affect tumorigenic development by regulating growth factor binding, signal transduction and cell cycle progression. Several lines of evidence indicate that aberrant expression of PGs is closely related to neovascularization, epithelial-to-mesenchymal transition (epithelial-MESENCHYMAL TRANSITION, EMT), and immune escape. Beta-1,3-glucuronyl transferase 3 (beta-1, 3-glucuronyltransferase, B3GAT 3) is taken as the speed limiting enzyme of GAG synthesis initial step, and is responsible for transferring glucuronic acid (GlcA) to a core protein to be connected with a tetrasaccharide framework, thus being a key node for obtaining biological activity of PGs. Functional deletion studies confirm that GAG chain synthesis is not completely detected in embryonic fibroblasts of whole-body knockout B3GAT3 mice, whereas the PGs yield was restored to 2.1 fold that of wild-type after complementation of the enzyme cDNA to B3GAT 3-deficient CHO mutants, suggesting that expression levels and PGs abundance are dose-dependent. Clinical sample analysis further showed that B3GAT3 was highly expressed in approximately 65% of HCC tissues and was significantly positively correlated with microvascular invasion, satellite nodules, and early postoperative recurrence (p < 0.01). In vitro functional experiments show that after the CRISPR-Cas9 is adopted to knock down the B3GAT3 of the HepG2 cell, the proliferation rate of the cell is reduced by 42%, the migration and invasion capacities are respectively reduced by 55% and 48%, and the cell cycle and EMT program are regulated to drive the tumor to progress along with the down regulation of the expression of Cyclin D1 and MMP-2/9 and the up regulation of E-cadherein. In conclusion, the B3GAT3 mediated PGs synthesis pathway not only provides a new metabolism-apparent cross regulation axis for HCC, but also is expected to become a substitute intervention node for overcoming the drug resistance and toxicity bottlenecks of multi-kinase inhibitors. Aiming at the enzyme, a high-selectivity small molecule inhibitor or PROTAC degradation agent is developed, so that not only can the tumor angiogenesis and malignant proliferation be blocked, but also the systemic toxicity caused by the inhibition of pan-kinase can be avoided, and the enzyme has remarkable clinical transformation potential and public health value. Disclosure of Invention The invention aims at providing a (4- (6-methoxyquinoline-4-carbonyl) -1-yl) and-1, 2-diketone compound and pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition or a B3GAT3 inhibitor taking the compound and pharmaceutically acceptable salt thereof as active ingredients, and a fourth aim at providing a pharmaceutical appl