Novel Substituted Exomethylene-oxindoles as HPK1 Inhibitors.

pubs.acs.org/acsmedchemlett Patent Highlight Novel Substituted Exomethylene-oxindoles as HPK1 Inhibitors Ram W. Sabnis* Cite This: ACS Med. Chem. Lett. 2021, 12, 681−682 ACCESS ■ Read Online Metrics & More Article Recommendations IMPORTANT COMPOUND CLASSES The present application describes a series of novel substituted exomethylene-oxindoles as HPK1/MAP4K1 inhibitors for the treatment of hepatitis B virus (HBV) infection, human immunodeficiency virus (HIV) infection, and cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment. Definitions. A = N or CR1; R1, R2, and R3 = H, halogen, CN, -N(R13)2, C1−C3 alkyl, C1−C3 haloalkyl, C2−C3 alkynyl, C1−C3 alkoxy, or SO2R13, wherein the C2−C3 alkynyl is unsubstituted or substituted with 1, 2, or 3 R9 groups; one of the B and E is and the other is J; Title. Substituted Exomethylene-oxindoles Which Are HPK1/MAP4K1 Inhibitors Patent Publication Number. WO 2020/237025 A1 Publication Date. November 26, 2020 Priority Application. US 62/851,875 Priority Date. May 23, 2019 Inventors. Aktoudianakis, E.; Chandrasekhar, J.; Codelli, J. A.; Conway, J. H.; Elbel, K. M.; Kalla, R. V.; Metobo, S. E.; Mitchell, S. A.; Perry, T.; Simonovich, S. P.; Ziebenhaus, C. A. Assignee Company. Gilead Sciences, Inc., USA Disease Area. HBV, HIV, and cancer Biological Target. Hematopoietic progenitor kinase 1 (HPK1) (MAP4K1) Summary. Immuno-oncology is an active area of cancer research, highlighted by inhibitor antibodies against the immune checkpoint receptors CTLA4, PD-1, and PD-L1. Targeted disruption of these checkpoint pathways releases the immune cell from key regulatory pathways, promoting an increase in immune response against cancer cells. Current therapies utilizing these checkpoint inhibitors are highlighted by significant and durable responses to many different cancers. Hematopoietic progenitor kinase 1 (HPK1), a STE20 ser/ thr kinase from the germinal center family of kinases, regulates the function of diverse immune populations, including T cells, B cells, and dendritic cells. In T cells, it negatively regulates T cell receptor (TCR) signaling by phosphorylating SLP76 on serine 376. Association of SLP76 with 14-3-3 protein subsequently leads to dissociation of the signaling complex. Further, supporting the role of HPK1 as a negative regulator of TCR signaling, murine HPK1 deficient T cells or HPK1 kinase inactive mutant T cells have enhanced ERK 1/2 activation and effector cytokine secretion upon TCR activation compared to their wild-type counterparts. Accordingly, a small molecule inhibitor of HPK1 could offer a method for increasing the response to checkpoint receptor blockade therapy. Published 2021 by American Chemical Society is a group of formulae: wherein L1 = N or CR19; n = 0, 1, or 2; m = 0, 1, or 2; p = 0, 1, 2, 3, 4, 5, or 6; R20 = -OR13, halogen, CN, -N(R13)2, or C1−C3 alkyl; and R21 = -OR13, oxo, halogen, CN, -N(R13)2, or C1−C3 alkyl. Received: March 28, 2021 Published: April 13, 2021 681 https://doi.org/10.1021/acsmedchemlett.1c00172 ACS Med. Chem. Lett. 2021, 12, 681−682 ACS Medicinal Chemistry Letters pubs.acs.org/acsmedchemlett Key Structures. ■ Patent Highlight 5. Sawasdikosol, S.; Burakoff, S. eLife 2020, 9, e55122. 6. Chuang, H.; Tan, T. J. Biomed. Sci. 2019, 26, 82. AUTHOR INFORMATION Corresponding Author Ram W. Sabnis − Smith, Gambrell & Russell LLP, Atlanta, Georgia 30309, United States; orcid.org/0000-00017289-0581; Email: Complete contact information is available at: https://pubs.acs.org/10.1021/acsmedchemlett.1c00172 Notes The author declares no competing financial interest. Biological Assay. The human hematopoietic progenitor kinase 1 (HPK1) (MAP4K1) biochemical assay was performed. The compounds described in this application were tested for their ability to inhibit HPK1. The HPK1 IC50 (nM) are shown in the following Table. Biological Data. The Table below shows representative compounds were tested for HPK1 inhibition. The biological data obtained from testing representative examples are listed in the following Table. Claims. Total claims: 167 Compound claims: 119 Pharmaceutical composition claims: 7 Method of treatment claims: 18 Method of inhibition claims: 6 Method of increasing T-cell activation claims: 1 Use of compound claims: 16 Recent Review Articles. 1. Safa, A.; Abak, A.; Shoorei, H.; Taheri, M.; GhafouriFard, S. Biomed. Pharmacother. 2020, 132, 110853. 2. Fu, L.; Cui, C.; Zhang, X.; Zhang, L. Semin. Cancer Biol. 2020, 67, Part 2, 102. 3. Zheng, J.; Wu, J.; Ding, X.; Shen, H. C.; Zou, G. Bioorg. Med. Chem. Lett. 2021, 38, 127862. 4. Ernst, M. P. T.; Broeders, M.; Herrero-Hernandez, P.; Oussoren, E.; van der Ploeg, A. T.; Pim Pijnappel, W. W. M. Mol. Ther. − Methods Clin. Dev. 2020, 18, 532. 682 https://doi.org/10.1021/acsmedchemlett.1c00172 ACS Med. Chem. Lett. 2021, 12, 681−682  (...truncated)