MACROCYCLE COMPOUNDS USEFUL AS KRAS INHIBITORS

Smart overview of the Invention

The invention pertains to macrocycle compounds that serve as inhibitors of KRAS, a well-known proto-oncogene implicated in approximately 30% of human cancers. These compounds are specifically designed to target mutations in KRAS, which are prevalent in colorectal, pancreatic, and lung cancers. The compounds are based on a specific formula and include various substituents such as R1 to R6, A1, and A2. These compounds can exist in their pharmaceutically acceptable salt forms and are intended for use in therapeutic compositions.

Field of Application

KRAS is a critical oncogenic driver with mutations that lead to cancer progression by activating the MAPK signaling pathway. The invention targets these mutations, particularly those at positions 12, 13, 61, and 146, which contribute to hyperactivation of the pathway. Despite the development of drugs like AMG510 for KRAS G12C mutations, resistance often develops. Therefore, new therapies targeting a broader range of KRAS mutations are urgently needed.

Compound Details

The compounds described are characterized by their ability to inhibit KRAS effectively, particularly the G12C and G12V mutations. They demonstrate superior cancer cell inhibition and stability in human hepatocytes compared to existing treatments. The compounds also exhibit favorable cytotoxicity, solubility profiles, and pharmacokinetic properties. The invention includes methods for synthesizing these compounds and their potential use as medicaments.

Definitions and Chemical Structure

The document provides detailed definitions for various chemical groups involved in the compound's structure. These include terms like "C1-6alkyl," "halogen," "thiazolylene," and others that describe the molecular building blocks of the compounds. Understanding these terms is essential for comprehending the chemical characteristics and potential modifications of the compounds.

Pharmaceutical Considerations

The invention includes pharmaceutically acceptable salts of the compounds, which are crucial for ensuring their safety and efficacy as medications. These salts can be formed with both inorganic and organic acids or bases, enhancing the compounds' therapeutic potential. Additionally, the document mentions active metabolites that result from metabolic processes within the body, highlighting their importance in achieving therapeutic effects.