Novel Isoindolone Compounds as HPK1 Inhibitors for Treating Cancer.

pubs.acs.org/acsmedchemlett Patent Highlight Novel Isoindolone Compounds as HPK1 Inhibitors for Treating Cancer Ram W. Sabnis* Cite This: ACS Med. Chem. Lett. 2022, 13, 156−157 ACCESS Read Online Metrics & More Article Recommendations Important Compound Classes. of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment. Definitions. R1 = H, halogen, (C1−C6)alkyl, halo(C1− C6)alkyl, (C1−C6)alkoxy, halo(C1−C6)alkoxy, −N(R6)(R7), −SO2CH3, (C3−C6)cycloalkyl, (C3−C6)cycloalkoxy, (4- to 6membered)-heterocycloalkyl and 5- to 6-membered)heteroaryl, wherein (C1−C6)alkyl, halo(C1−C6)alkyl, (C1−C6)alkoxy, (C3−C6)cycloalkoxy, (4- to 6-membered)-heterocycloalkyl, (5- to 6-membered)heteroaryl, and (C3−C6)cycloalkoxy are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, CN, (C1−C6)alkyl, halo(C1− C6)alkyl, (C1−C6)alkoxy, halo(C1−C6)alkoxy, and −N(R6)(R7); R2 = H; −(CH2)mN(R8)(R9), wherein m = 0−3; (C1− C6)alkyl, wherein (C1−C6)alkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, (C 1 −C 6 )alkoxy, CN and OH; (4- to 6-membered)heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, CN, (C1−C6)alkyl, halo(C1− C6)alkyl, (C1−C6)alkoxy, and halo(C1−C6)alkoxy; R3 = H, halogen, OH, (C1−C6)alkyl, halo(C1−C6)alkyl, (C1− C6)alkoxy, and halo(C1−C6)alkoxy; X = carbon or nitrogen; R4 = (C1−C6)alkyl, (C1−C6)alkoxy, −C(O)N(R10)(R11), (C6−C10)aryl, −O-(C6−C10)aryl, (C3−C6)cycloalkyl, −O(C 3 −C 6 )cycloalkyl, NH-(C 3 −C 6 )cycloalkyl, 4- to 6membered)heterocycloalkyl, (5- to 10-membered)heteroaryl, wherein (C1−C6)alkyl, (C1−C6)alkoxy, −C(O)N(R10)(R11), (C6−C10)aryl, −O-(C6−C10)aryl, (C3−C6)cycloalkyl, −O(C 3 −C 6 )cycloalkyl, NH-(C 3 −C 6 )cycloalkyl, 4- to 6membered)heterocycloalkyl, (5- to 10-membered)heteroaryl, wherein cycloalkoxy are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, OH, CN, oxo, (C1−C6)alkyl, halo(C1−C6)alkyl, (C1−C6)alkoxy, halo(C1 −C 6 )alkoxy, −N(R 6)(R 7), −SO 2 CH 3, (C 3−C6)cycloalkyl, (C3−C6)cycloalkoxy, (4- to 6-membered)-heterocycloalkyl; Title. Isoindolone Compounds as HPK1 Inhibitors Patent Publication Number. WO 2021/224818 A1 Publication Date. November 11, 2021 Priority Application. US 63/021,844 Priority Date. May 8, 2020 Inventors. Ahmad, O.; Delbel, M. L.; Dress, K. R.; Gallego, R. A.; He, M.; Jalaie, M.; Johnson, T. W.; Kania, R. S.; McTigue, M. A.; Nair, S. K.; Tuttle, J. B.; Zhou, D.; Zhou, R. Assignee Company. Pfizer Inc., USA Disease Area. Cancer Biological Target. Hematopoietic progenitor kinase 1 (HPK1) (MAP4K1) Summary. Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a member of the mammalian Ste20-like family of serine/threonine kinases that operates via the JNK and ERK signaling pathways. HPK1 is mainly expressed in hematopoietic organs/cells (e.g., T-cells, B-cells, and dendritic cells), suggesting potential involvement of HPK1 in the regulation of signaling hematopoietic lineages including lymphocytes. For example, stimulation of the T-cell receptor (TCR) induces HPK1 tyrosine 379 phosphorylation and relocation of plasma membrane. Enzymatic activation of HPK1 is accompanied by phosphorylation of regulatory sites in the HPK1 kinase activation loop. HPK1 kinase has been reported to play roles in (i) activation-induced cell death (AICD) and JNK activation; (ii) regulation of leukocyte function-associated antigen-1 (LFA-1) integrin activation of T-cells by direct competition with adhesion and deregulation promoting adaptor protein (ADAP) for binding of the SLP76 SH2 domain; and (iii) regulation of activation via nuclear factor kB signaling and interacting with IKK-α and β. HPK1 inhibition plays a role in enhancing dendritic and T-cell responses and thereby heightening antitumor immunity, virus clearance, and response to vaccine therapy. The present application describes a series of novel isoindolone compounds as HPK1 inhibitors for the treatment Published 2022 by American Chemical Society Received: December 28, 2021 Published: January 12, 2022 156 https://doi.org/10.1021/acsmedchemlett.1c00725 ACS Med. Chem. Lett. 2022, 13, 156−157 ACS Medicinal Chemistry Letters pubs.acs.org/acsmedchemlett R5 = H, halogen, OH, (C1−C6)alkyl, halo(C1−C6)alkyl, (C1− C6)alkoxy, halo(C1−C6)alkoxy; and a = 0 or 1. Key Structures. ■ Patent Highlight 4. Alves, E.; Taifour, S.; Dolcetti, R.; Chee, J.; Nowak, A. K.; Gaudieri, S.; Blancafort, P. Mol. Ther. - Methods Clin. Dev. 2021, 21, 592. 5. Sawasdikosol, S.; Burakoff, S. eLife 2020, 9, e55122. 6. 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. 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.1c00725 Notes The author declares no competing financial interest. Biological Assay. The human hematopoietic progenitor kinase 1 (HPK1) (MAP4K1) biochemical enzyme assay was performed. The compounds described in this application were tested for their ability to inhibit HPK1. The HPK1 Ki (μM) 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: 14 Compound claims: 12 Pharmaceutical composition claims: 1 Method of treatment claims: 1 Recent Review Articles. 1. Zheng, J.; Wu, J.; Ding, X.; Shen, H. C.; Zou, G. Bioorg. Med. Chem. Lett. 2021, 38, 127862. 2. Kong, H.; Ju, E.; Yi, K.; Xu, W.; Lao, Y.; Cheng, D.; Zhang, Q.; Tao, Y.; Li, M.; Ding, J. Adv. Sci. 2021, 8, 2102051. 3. Bhanja, A.; Rey-Suarez, I.; Song, W.; Upadhyaya, A. FEBS J. 2022, in press. 157 https://doi.org/10.1021/acsmedchemlett.1c00725 ACS Med. Chem. Lett. 2022, 13, 156−157  (...truncated)