Novel Substituted Indazoles as Small Molecule-Based Inhibitors of KRAS Proteins

Abstract

This patent discloses a series of substituted indazole compounds as novel inhibitors of KRAS, with potential utility as anticancer therapeutics. The invention describes the chemical structures of these substituted indazoles, their pharmaceutical compositions, and methods of use for treating KRAS-driven malignancies. The disclosed compounds are designed to modulate oncogenic KRAS signaling and may offer a new therapeutic strategy for cancers associated with KRAS mutations.

Important Compound Classes

Title

Indazole containing compounds and methods of use

Patent Publication Number

WO 2025/136346 A1, URL: https://patents.google.com/patent/WO2025136346A1/en

Publication Date

June 26, 2025

Priority Application

PCT/US2023/074842

Priority Date

December 19, 2023

Inventors

Pettus, L.; Smaligo, A.; Li, X.; Yamano, M.; Emmetiere, F.; Amegadzie, A.; Li, Y.; Jackson, J.; Medina, J.; Navaratne, P.; Wurz, R.; Chen, N.; Zhao, W.; Rahimoff, R.; Rui, H.; Lanman, B.; Siegmund, A.

Assignee Company

Amgen Inc. [US/US]; 1 Amgen Center Drive, Thousand Oaks, California, 91320–1799, United States

Disease Area

Cancers

Biological Target

Kirsten rat sarcoma viral oncogene (KRAS)

Summary

RAS (rat sarcoma viral oncogene) is the gene that encodes guanosine triphosphate (GTP) kinases, which have vital roles in cell growth, differentiation, and survival. As a well-known mutated oncogene, RAS is mutated in approximately 20% of all human cancers.

KRAS is the main type of RAS, and its mutations are frequently found pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and nonsmall-cell lung cancer (NSCLC). Though its clinical importance, the KRAS has long been considered undruggable due to the lack of binding pockets and high binding affinity toward GTP, which is present at abundant levels in the cell. Recent advances in structural biology have enabled the development of KRAS inhibitors, including sotorasib and adagrasib. However, effective treatments for other KRAS mutations remain an unmet medical need.

This patent seeks to develop novel and potent KRAS inhibitors with various types of KRAS mutations. Novel substituted pyrido­[4,3-d]­pyrimidines, pharmaceutical compositions, and the uses of such compounds in the treatment of cancers, are disclosed in this patent.

Definitions

X = CH₂, O, S, S­(O), S­(O)­(NR^z), or S­(O)₂;

n = 0, 1, 2, or 3;

m = 0, 1, 2, or 3;

p = 0, 1, 2, 3, or 4;

R^x = OH, halogen, O, CN, -N­(R^z)₂, C_1–4 alkyl, C_1–4 alkoxy, C_1–4 haloalkyl, C_1–4 haloalkoxy, 5–7 membered heteroaryl, -T-R^y, or two R^x taken together with the same carbon or adjacent carbon atoms can form C_3–7 cycloalkyl or 3–7 membered heterocycloalkyl, wherein each C_3–7 cycloalkyl or 3–7 membered heterocycloalkyl is further substituted with 0–3 occurrences of R^y or two R^x taken together can form a bridged ring where the bridge is selected from one of the following: -C_1–4 alkylene-, -C_1–4 alkylene–O-C_1–4 alkylene-, -O-, -S-, or -C_1–4 alkylene–S-C_1–4 alkylene- and wherein each C_1‑4 alkylene is further substituted with 0–2 occurrences of R^y;

L = C_1–6 alkylene, −O-C_1–6 alkylene, −S-C_1–6 alkylene, NR^z, O, or S, wherein each C_1–6 alkylene, −O-C_1–6 alkylene, and −S-C_1–6 alkylene chain is substituted with 0–2 occurrences of R²;

R¹ = OH, N­(R^z)₂, aryl, heteroaryl, C_3–8 cycloalkyl, or heterocycloalkyl substituted with 0–3 occurrences of R⁵;

R² = halogen, OH, C_1–4 alkyl or two R² on the same or adjacent carbon atoms can be taken together to form a C_3–7 cycloalkyl;

R³ = aryl or heteroaryl substituted with 0–3 occurrences of R⁶;

R⁴ = H, OH, halogen, C_1–4 alkyl, C_1–4 alkoxy, C_1–4 haloalkyl, C_2–4 alkenyl, C_2–4 alkynyl, C_3–7 cycloalkyl, or CN;

R⁵ = halogen, CN, O, -T-R^y, OH, amino, or C_1–4 alkyl;

R⁶ = halogen, OH, CN, -N­(R^z)₂, C_1–4 alkyl, C_1–4 alkoxy, C_1–4 haloalkyl, C_1–4 haloalkoxy, C_2–4 alkynyl, or C_3–6 cycloalkyl;

R⁷ = halogen, C_1–6 alkyl, C_2–6 alkenyl, C_1–4 alkoxy, C_1–4 haloalkyl, or C_3–7 cycloalkyl wherein each alkyl, alkenyl, or cycloalkyl is further substituted by 0–2 occurrences of R^w;

R⁸ = H, halogen, C_1–4 alkyl, C_1–4 haloalkyl, or C_2–6 alkenyl; or R⁷ and R⁸ are taken together with the atoms to which they are connected to form a C_3–7 cycloalkyl or 3–7 membered heterocycloalkyl substituted with 0–3 occurrences of R^w;

R⁹ = H, halogen, or C_1–4 alkyl;

R¹⁰ = H, halogen, OH, C_1–4 alkyl, -T-R^y, or C_1–4 haloalkyl;

R¹² = H, -C­(O)-C_1–4 alkyl, -C­(O)-C_1–4 alkoxy, C_1–4 alkylene-O-C­(O)-C_1–4 alkyl, or -C_1–4 alkylene-C­(O)-C_1–4 alkyl;

R^w = halogen, OH, C_1–4 alkyl, C_1–4 haloalkyl, C_1–4 alkoxy, or C_3–6 cycloalkyl;

T = C_1–4 alkylene, -S­(O)₂-, -C­(O)-, -C_1–4 alkylene-C­(O)-, C_1–4 alkylene-S­(O)₂-, or - S-;

R^y = halogen, O, C_1–4 alkyl, C_1–4 haloalkyl, OH, CN, or -N­(R^z)₂;

R^z = H or C_1–4 alkyl.

Key Structures

Biological Assay

In vitro time-resolved fluorescence resonance energy transfer (TR-FRET) assays were performed to investigate the activity of compounds from this patent for inhibiting KRAS G12D. The IC₅₀ values (μM) of some representative examples are shown below.

Biological Data

Claims

Total claims: 55

Compound claims: 49

Pharmaceutical composition claims: 2

Use of compound claims: 2

Method of treatment claims: 2

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The authors declare no competing financial interest.