Novel Indazole Compounds as PKMYT1 Kinase Inhibitors for Treating Cancer

Abstract

Provided herein are novel indazole compounds as PKMYT1 kinase inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Important Compound Classes

Title

Indazole Compounds

Patent Publication Number

WO 2026/037849 A1

URL

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2026037849&_cid=P20-MM6VJJ-46017-1

Publication Date

February 19, 2026

Priority Application

CN PCT/CN2024/112340

Priority Date

August 15, 2024

Inventors

Chen, B.; Liu, X.; Tan, X.; Wu, J.; Xu, J.; Zhao, D.

Assignee Company

F. Hoffmann-La Roche AG, Switzerland and F. Hoffmann-La Roche Inc., USA

Disease Area

Cancer

Biological Target

PKMYT1 Kinase

Summary

Cells are frequently experiencing both intrinsic and extrinsic genotoxic stresses that cause DNA damage and impair the integrity of genome. To counter the potential genetic alterations caused by these DNA-damaging factors, cells need to establish various mechanisms to detect DNA lesions and repair DNA damage to maintain genome stability. This sophisticated network, referred to as the DNA damage response (DDR), is orchestrated by multiple highly evolutionary conserved and coordinated signaling pathways that can correct different types of DNA lesions. One essential component involved in DDR machinery is the activation of cell cycle checkpoints that arrest the cell cycle at a specific stage until damaged DNA has been required. At least two types of checkpoints, G1/S and G2/M, participate in DDR signaling.

In cancer cells, genome instability and replication stress are commonly observed due to the dysregulation of DDR machinery usually induced by endogenous genetic alterations of cancer cells or genotoxic agents. For example, G1/S checkpoints such as p53, are frequently mutated and disrupted in cancer cells. As a result, the survival of cancer cells bearing replication stress and dysfunctional G1/S checkpoints highly depends on G2/M checkpoints for the processing of DNA damage repair. Therefore, disruption of the G2/M checkpoint via protein kinase, membrane-associated tyrosine and threonine kinase (PKMYT1) kinase activity inhibition has become a promising therapeutic approach especially for genetically targeted cancer therapies.

The present application describes a series of novel indazole compounds as PKMYT1 kinase inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = H or halogen; and

Key Structures

Biological Assay

The ADP-Glo PKMYT1 kinase assay was performed. The compounds described in this application were tested for their ability to inhibit PKMYT1 kinase. The PKMYT1 IC₅₀ (nM) values are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested for PKMYT1 inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 21

Compound claims: 13

Pharmaceutical composition claims: 1

Method of preparation claims: 1

Method of treatment claims: 1

Use of compound claims: 5

Recent Review Articles

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The author declares no competing financial interest.