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CN-122029171-A - Small molecule inhibitors of KRAS proteins

CN122029171ACN 122029171 ACN122029171 ACN 122029171ACN-122029171-A

Abstract

The compounds of formulas (I) to (VII), or pharmaceutically acceptable salts thereof, inhibit the G12C, G12D, G V and/or G13D mutant of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example for the treatment of cancer. The present disclosure also provides pharmaceutical compositions comprising compounds of formulas (I) through (VII), or pharmaceutically acceptable salts thereof. The present disclosure also relates to methods of using these compounds, or pharmaceutically acceptable salts thereof, for the treatment and prevention of cancer and for the preparation of medicaments for this purpose.

Inventors

  • S. KAWAMURA
  • Xiao Zao Chuan you
  • Ohga Tsuyoshi
  • UNO YOSHIO
  • P. Schoff

Assignees

  • 默沙东有限责任公司

Dates

Publication Date
20260512
Application Date
20241018
Priority Date
20231020

Claims (20)

  1. 1. A compound selected from the group consisting of: (III)、 (IV)、 (VI) (VII), Or a pharmaceutically acceptable salt thereof.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (III)。
  3. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (IV)。
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (VI)。
  5. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is (VII)。
  6. 6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  7. 7. A pharmaceutical composition comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, an additional anticancer agent, and a pharmaceutically acceptable carrier.
  8. 8. A method of inhibiting a KRAS-G12D protein comprising contacting a KRAS-G12D protein with a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12D protein.
  9. 9. A method of inhibiting a KRAS-G12C protein comprising contacting a KRAS-G12C protein with a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12C protein.
  10. 10. A method of inhibiting a KRAS-G12V protein comprising contacting a KRAS-G12V protein with a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G12V protein.
  11. 11. A method of inhibiting a KRAS-G13D protein comprising contacting a KRAS-G13D protein with a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, to inhibit the activity of the KRAS-G13D protein.
  12. 12. A method of treating cancer comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
  13. 13. The method of claim 12, further comprising administering to the subject an additional active agent.
  14. 14. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in therapy, or a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in therapy.
  15. 15. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, or a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  16. 16. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, or a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
  17. 17. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and an additional anticancer agent for use in the treatment of cancer, or the use of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and an additional anticancer agent for the treatment of cancer.
  18. 18. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and an additional anticancer agent for the manufacture of a medicament for the treatment of cancer, or a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and an additional anticancer agent for the manufacture of a medicament for the treatment of cancer.
  19. 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and an additional anticancer agent for use in the treatment of cancer, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and an additional anticancer agent for use in the treatment of cancer.

Description

Small molecule inhibitors of KRAS proteins Cross reference to related applications The present application claims the benefit of U.S. provisional application Ser. No. 63/591,871, filed on 10/20/2023, ser. No. 63/638,789, filed on 25/4/2024, and Ser. No. 63/680,205, filed on 8/2024, the disclosures of which are incorporated herein by reference in their entirety. Technical Field The present disclosure relates to small molecule inhibitors of KRAS that inhibit G12C mutants, G12D mutants, G12V mutants, G13D mutants, and Wild Type (WT) of, for example, kirsten rat sarcoma (KRAS) proteins, and to pharmaceutical compositions comprising compounds of formulas (I) to (VII) and methods of using the compounds to treat diseases, including cancer. Background RAS, which is a small monomeric GTP-binding protein having a molecular weight of about 21 kDa, acts as a molecular on/off switch. RAS can bind to GTP through proteins that bind to the guanine nucleotide exchange factor (GEF) (e.g., SOS 1), which forces release of the bound nucleotides and release of GDP. When the RAS binds to GTP, it becomes activated (opened) and recruits and activates proteins required for the transmission of signals for other receptors, such as c-Raf and PI 3-kinase. RAS also has enzymatic activity, with which it cleaves the terminal phosphate of a GTP nucleotide and converts that nucleotide to GDP. The rate of conversion is typically slow, but can be dramatically accelerated by a protein of the gtpase-activating protein (GAP) class, such as RasGAP. When GTP is converted to GDP, RAS is deactivated (turned off). Members of the commonly known RAS subfamilies include HRAS, KRAS and NRAS. Among these, mutations in KRAS were observed in 86% of Pancreatic Ductal Adenocarcinomas (PDACs), in 41% of colorectal carcinomas (CRCs) and in 32% of lung adenocarcinomas (LUAD; subtype of non-small cell lung carcinoma (NSCLC)). Mutations frequently occur at glycine residues at position 12 ("G12") of KRAS, mutations at G12 account for 91% (PDAC), 68% (CRC) and 85% (LUAD), respectively, of the total KRAS mutation. The distribution of amino acid substitutions at G12 varies between each tissue type. The most common mutation in LUAD is to cysteine ("G12C") (46%), while the dominant mutation in PDAC (45%) and CRC (45%) is to aspartic acid ("G12D"). Mutations to valine at G12 ("G12V") were observed in a significant portion of the G12 mutations in all PDACs (35%), CRCs (30%), and LUADs (23%). (Nature Reviews Drug Discovery,19,533-552,2020). KRAS-G12C inhibitors are being developed vigorously. Several covalent inhibitors focused on cysteine residues have been reported, and some of them have undergone clinical studies such as AMG510 (NCT 03600883), MRTX849 (NCT 03785249) and JNJ-74699157 (NCT 04006301). However, KRAS-G12C mutations account for only a portion of all KRAS mutations and are found predominantly in LUAD. In order to effectively inhibit other commonly occurring KRAS muteins, such as KRAS-G12D and KRAS-G12V, different pathways are required, as these mutants lack reactive cysteines in the active site (Nature Reviews Drug Discovery,19,533-552,2020). Studies have also indicated that gene amplification and high expression of WT KRAS in the absence of coding mutations may also occur in certain cancers. These amplifications are most frequently observed in esophageal, gastric, and ovarian adenocarcinomas (24,968-977,2018). Thus, effective inhibition of WT KRAS may provide therapeutic benefit to patients suffering from such cancers. Disclosure of Invention The present disclosure provides small molecule inhibitors of regulatory mutant and WT KRAS proteins and may be valuable pharmaceutically active compounds for the treatment of cancer. In some embodiments, the disclosed compounds selectively inhibit KRAS-G12C, KRAS-G12D and/or KRAS-G12V proteins. Compounds of formulae (I) to (VII): (I)、 (II)、 (III)、 (IV)、 (V)、 (VI) (VII) And pharmaceutically acceptable salts thereof, can modulate KRAS activity and thereby affect signaling pathways that regulate cell growth, differentiation and proliferation associated with neoplastic disorders. In certain embodiments, compounds of formulas (I) through (VII) inhibit KRAS-G12C, KRAS-G12D, KRAS-G12V, KRAS-G13D and/or WT KRAS proteins. The present disclosure further provides methods for preparing compounds of formulas (I) through (VII), methods of using such compounds to treat neoplastic disorders, and pharmaceutical compositions comprising compounds of formulas (I) through (VII). The present disclosure also provides small molecule inhibitors of regulatory mutant and WT KRAS proteins and may be valuable pharmaceutically active compounds for the treatment of cancer. In some embodiments, the disclosed compounds selectively inhibit KRAS-G12C, KRAS-G12D and/or KRAS-G12V proteins. Compounds of formulae (III), (IV), (VI) and (VII): (III)、 (IV)、 (VI) (VII) And pharmaceutically acceptable salts thereof, can modulate KRAS activity and thereby affect sig