CN-117720556-B - Pan-KRAS inhibitor compound and preparation method and application thereof

Abstract

The invention relates to a KRAS inhibitor compound with the following structure, and a preparation method and application thereof.

Inventors

• CHEN YUFENG
• LV MENG
• LIU CANFENG
• CHENG WANLI
• LI FEIFAN
• YANG HAN
• CHEN KAIXUAN
• LIU SHUAISHUAI
• HE NANHAI

Assignees

• 杭州阿诺生物医药科技有限公司

Dates

Publication Date

20260505

Application Date

20230901

Priority Date

20220919

Claims (4)

1. 1. A KRas inhibitor compound having a structure selected from the group consisting of: 。
2. 2. a pharmaceutical composition comprising a compound according to claim 1.
3. 3. Use of a compound according to claim 1 and a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and/or treatment of a tumor, an inflammatory disease or an immune-mediated disease.
4. 4. Use of a compound according to claim 1 and a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the prevention and/or treatment of cancer, inflammatory diseases or autoimmune diseases.

Description

Pan-KRAS inhibitor compound and preparation method and application thereof Technical Field The invention relates to a compound, in particular to a pan-KRAS inhibitor with high activity, a preparation method and application thereof. Background RAS is one of the most frequently mutated genes in human tumors, which mutations occur in about 30% of tumor patients, with KRAS accounting for about 85% of RAS mutations. Mutations in KRAS exist in 88% of pancreatic cancers, 50% of colorectal adenocarcinomas and 32% of lung adenocarcinomas, and the development of targeted KRAS inhibitors is of great clinical significance and value. KRAS is a membrane-bound protein with gtpase activity that performs the function of "molecular switching" by cycling between a GDP-bound inactive conformation and a GTP-bound active conformation through nucleotide exchange. KRAS in GTP combined state can activate downstream multiple signal paths including RAF-MEK-ERK and PI3K-AKT, and regulate and control life processes such as cell growth, proliferation, differentiation, apoptosis and the like. KRAS mutations (e.g., G12C, G12D, G V, G D, etc.) affect gtpase activator protein (GTPASE ACTIVATING proteins, GAPs) -mediated GTP hydrolysis, increasing KRAS in the GTP-bound activated state, overactivating downstream signaling pathways, ultimately leading to tumor initiation and progression. However, due to the lack of a corresponding hydrophobic pocket suitable for drug binding in KRAS proteins, while their affinity for GTP and GDP is in the picomolar scale (20 pM), development of inhibitors that competitively bind KRAS has been difficult, and KRAS has been considered a non-patentable target in the last few decades. In month 2021, AMG510 was approved by the FDA for the treatment of locally advanced or metastatic non-small cell lung cancer harboring KRAS G12C mutations, breaking the history of KRAS "non-patentable". However, the G12C mutation is only a small part of KRAS mutation, and there is no satisfactory effective inhibitor compound for the mutation of other KRAS sites, and there is a great clinical demand that has not yet been satisfied, so that development of an effective pan-KRAS inhibitor compound is a need in the art. Disclosure of Invention The present invention provides a pan-KRAS inhibitor. Such structures are different from the prior KRAS G12C inhibitors which act by covalent binding, but rather by mediating the formation of ternary complexes with the KRAS proteins of chaperones (e.g. cyclopylin a) which are ubiquitous in cells. The ternary complex can block the combination of KRAS and downstream effector molecules (such as RAF) through steric hindrance, inhibit the activation of MAPK and PI3K-AKT signal paths, further inhibit the occurrence and development of tumors, and play a role in treating diseases such as tumors. In one aspect, the invention provides a KRas inhibitor compound having a structure selected from the group consisting of: In some embodiments of the invention, the compounds are prepared by intermediate compound INT-4: in some embodiments of the present invention, the preparation of intermediate compound INT4 comprises the steps of: The preparation method comprises the steps of dissolving a compound INT-3a and a compound INT-4a in dichloromethane, adding N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate and 1-methylimidazole at 0 ℃, reacting for 1 hour, monitoring that raw materials are completely reacted by LCMS, pouring reaction liquid into water, extracting with dichloromethane, washing an organic phase with water, mixing and purifying by a column to obtain a white solid compound INT-4b, and the second step comprises dissolving the compound INT-4b, 2-dicyclohexylphosphine-2 ',6' -dimethyl-biphenyl, tris (dibenzylideneacetone) dipalladium and potassium acetate in toluene, adding pinacol borane under the protection of nitrogen, reacting for 3 hours at 50 ℃ under the protection of nitrogen, monitoring that the raw materials are completely reacted by LCMS, filtering the reaction liquid, and purifying by silica gel column chromatography to obtain the yellow solid compound INT-4. In some embodiments of the invention, the preparation of compound 41 comprises the steps of: The first step is to dissolve the intermediate INT-4 and the intermediate INT-36 in a mixed solvent of 1, 4-dioxane and water, add 1, 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride and potassium phosphate, heat to 70 ℃ after the nitrogen is replaced by the system, stir for 12 hours, cool the reaction solution to room temperature, filter the reaction solution with diatomite, and concentrate the filtrate. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=30/1) to give compound 41a, and in the second step, compound 41a was dissolved in DMF, cesium carbonate was added, ethyl iodide was then added dropwise to the reaction solution, the reaction solution was stirred at room tem