Novel Tetrahydropyrido[3,4-d]pyrimidines as HPK1 Inhibitors for Treating Cancer, Inflammatory, and Autoimmune Diseases

Abstract

Provided herein are novel tetrahydropyrido[3,4-d]pyrimidines as HPK1 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, inflammatory, and autoimmune diseases, and processes for preparing such compounds.

Important Compound Classes

Title

Tetrahydropyrido[3,4-d]pyrimidines Compounds as HPK1 Inhibitors

Patent Publication Number

WO 2023/220541 A1

URL: https://patents.google.com/patent/WO2023220541A1/en

Publication Date

November 16, 2023

Priority Applications

US 63/340,191 and US 63/383,190

Priority Dates

May 10, 2022, and November 10, 2022

Inventors

Toure, M.; Li, B.; Neagu, C.; Wang, Y.; Johnson, T.; Unzue-Lopez, A.; Xiao, Y.; Friis, E.; Dipoto, M.; Guler, S.

Assignee Company

Merck Patent GmbH, Germany

Disease Area

Cancer, inflammatory, and autoimmune diseases

Biological Target

HPK1

Summary

Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase expressed in T cells, B cells, and dendritic cells. In T cells, HPK1 acts as a rheostat of T cell activation by regulating the molecular circuits of the T cell receptor (TCR) signaling pathway. HPK1 is recruited to the TCR complex and phosphorylates SLP76 protein, leading to its degradation and down-modulation of TCR signal strength. Genetic ablation of HPK1 results in T cell activation, lower T cell threshold, increase proliferation, and elevated levels of inflammatory cytokines such as IL-2, TNF-α, and IFN-γ. Loss of HPK1 expression enhances dendritic cell activation and antigen presentation. HPK1 knockout (KO) and kinase dead (KD) mice show enhanced T cell function and antitumor efficacy.

The present application describes a series of novel tetrahydropyrido[3,4-d]pyrimidines as HPK1 inhibitors for treating cancer, inflammatory, and autoimmune diseases. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

R₁ and R₂ = H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, and C₁–C₆ haloalkyl;

R₃ = H and C₁–C₆ alkyl;

R₄ = H, halogen, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, and C₁–C₆ haloalkyl;

R₅ and R₆ = H, halogen, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, and C₁–C₆ haloalkyl; R₇ = H and C₁–C₆ alkyl;

X = N and CH; Y = N and CH;

W = N and CR₈; Z = N and CH; and

R₈ and R₉ = H, halogen, optionally C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₁–C₆ haloalkyl, C₂–C₈ heterocyclic, heteroaromatic, and C₆–C₁₄ aromatic.

Key Structures

Biological Assay

The HPK1 kinase biochemical assay was performed. The compounds described in this application were tested for their ability to inhibit HPK1. The HPK1 IC₅₀ values (nM) are shown in the following able.

Biological Data

The table below shows representative compounds that were tested for HPK1 inhibition and the biological data obtained from testing representative examples.For IC₅₀: A means < 100 nM.

Claims

Total claims: 69

Compound claims: 52

Pharmaceutical composition claims: 1

Method of treatment claims: 15

Kit claims: 1

Recent Review Articles

See refs (1−5).

The author declares no competing financial interest.