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

PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice editorial ACS Med Chem Lett . 2024 Jan 31;15(3):318–319. doi: 10.1021/acsmedchemlett.4c00023 Search in PMC Search in PubMed View in NLM Catalog Add to search Novel Tetrahydropyrido[3,4-d]pyrimidines as HPK1 Inhibitors for Treating Cancer, Inflammatory, and Autoimmune Diseases Ram W Sabnis Ram W Sabnis 1Smith, Gambrell & Russell LLP, 1105 W. Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States Find articles by Ram W Sabnis 1,* Author information Article notes Copyright and License information 1Smith, Gambrell & Russell LLP, 1105 W. Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States * E-mail: . Received 2024 Jan 13; Collection date 2024 Mar 14. Published 2024 by American Chemical Society PMC Copyright notice PMCID: PMC10945532 PMID: 38505843 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. References Li S.; Chen T.; Liu J.; Zhang H.; Li J.; Wang Z.; Shang G. PROTACs: Novel tools for improving immunotherapy in cancer. Cancer Lett. 2023, 560, 216128. 10.1016/j.canlet.2023.216128. [DOI] [PubMed] [Google Scholar] Villaruz L. C.; Blumenschein G. R.; Otterson G. A.; Leal T. A. Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death-ligand 1 inhibitors in non-small cell lung cancer. Cancer 2023, 129, 1319–1350. 10.1002/cncr.34683. 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