CN-117720555-B - Intermediate for preparing KRAS inhibitor compound and synthesis method thereof

Abstract

The invention relates to an intermediate compound for synthesizing a KRAS inhibitor compound with a structure shown in a formula INT-33 and a synthesis method 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 (5)

1. 1. An intermediate compound for the synthesis of KRAS inhibitor compounds having the structure of formula INT-33: INT-33。
2. 2. A process for the synthesis of the intermediate compound INT-33 as claimed in claim 1, comprising the steps of: Dissolving a compound INT-2, and sequentially adding INT-18, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride and potassium phosphate, filtering and purifying after the reaction is completed to obtain INT-33a; Dissolving the compound INT-33a, adding cesium carbonate and ethyl iodide, and extracting and purifying to obtain INT-33b after the reaction is completed; dissolving the compound INT-33b, adding p-toluenesulfonic acid monohydrate into the compound INT-33b, and extracting and purifying the compound INT-33c after the reaction is completed; And fourthly, dissolving the compound INT-33c, adding p-toluenesulfonyl chloride and potassium hydroxide into the solution, and purifying the solution after the reaction is completed to obtain the INT-33.
3. 3. The synthesis method as claimed in claim 2, wherein the synthesis of the compound INT-2 comprises the following steps: The first step is to dissolve the compound INT-1m, then add lithium hydroxide monohydrate, extract and purify the compound INT-2a after the reaction is completed; dissolving a compound INT-2a and a compound INT-2b, adding N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate and 1-methylimidazole at 0 ℃, reacting at 0 ℃ completely, and extracting and purifying to obtain a compound; the third step is to dissolve the compound INT-2c and then add lithium hydroxide monohydrate; Dissolving a compound INT-2d, 1-hydroxybenzotriazole and 4-dimethylaminopyridine, adding N, N-diisopropylethylamine at 0 ℃, and then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; And fifthly, dissolving the compound INT-2e, 2-dicyclohexylphosphine-2 ',6' -dimethyl-biphenyl, adding pinacol borane under the protection of nitrogen after dissolving tris (dibenzylideneacetone) dipalladium and potassium acetate, reacting at 50 ℃ under the protection of nitrogen after finishing the dropwise addition, and filtering and purifying to obtain the compound INT-2 after the reaction is finished.
4. 4. The synthesis method as claimed in claim 2, wherein the synthesis of the compound INT-18 comprises the following steps: Dissolving (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine INT-5a, sequentially adding cuprous iodide, bis (triphenylphosphine) palladium dichloride, triethylamine and INT-18 a, reacting under nitrogen protection, and purifying to obtain compound INT-5 after the reaction is completed.
5. 5. A KRAS inhibitor compound selected from the group comprising: 。

Description

Intermediate for preparing KRAS inhibitor compound and synthesis method thereof Technical Field The invention relates to a compound, in particular to an intermediate compound for preparing a pan-KRAS inhibitor with high activity. 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 present invention provides an intermediate compound for the synthesis of KRAS inhibitor compounds having the structure shown in formula INT-33: In one embodiment, a method for synthesizing intermediate compound INT-33 comprises the steps of: Dissolving a compound INT-2, and sequentially adding INT-18, [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride and potassium phosphate, filtering and purifying after the reaction is completed to obtain INT-33a; Dissolving the compound INT-33a, adding cesium carbonate and ethyl iodide, and extracting and purifying to obtain INT-33b after the reaction is completed; dissolving the compound INT-33b, adding p-toluenesulfonic acid monohydrate into the compound INT-33b, and extracting and purifying the compound INT-33c after the reaction is completed; And fourthly, dissolving the compound INT-33c, adding p-toluenesulfonyl chloride and potassium hydroxide into the solution, and purifying the solution after the reaction is completed to obtain the INT-33. Wherein the synthesis of the compound INT-2 comprises the following steps: The first step is to dissolve the compound INT-1m, then add lithium hydroxide monohydrate, extract and purify the compound INT-2a after the reaction is completed; dissolving a compound INT-2a and a compound INT-2b, adding N, N, N ', N' -tetramethyl chloroformyl amidine hexafluorophosphate and 1-methylimidazole at 0 ℃, reacting at 0 ℃ completely, and extracting and purifying to obtain a compound; the third step is to dissolve the compound INT-2c and then add lithium hydroxide monohydrate; Dissolving a compound INT-2d, 1-hydroxybenzotriazole and 4-dimethylaminopyridine, adding N, N-diisopropylethylamine at 0 ℃, and then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; And fifthly, dissolving the compound INT-2e, 2-dicyclohexylphosphine-2 ',6' -dimethyl-biphenyl, adding pinacol borane under the protection of nitrogen after dissolving tris (dibenzylideneacetone) dipalladium and potassium acetate, reacting at 50 ℃ under the protection of nitrogen after finishing the dropwise addition, and filtering and purifying to obta