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US-20260125366-A1 - METHODS FOR TREATING CANCER

US20260125366A1US 20260125366 A1US20260125366 A1US 20260125366A1US-20260125366-A1

Abstract

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, and compounds of Formula (II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

Inventors

  • David St. Jean, JR.
  • Natasja Brooijmans
  • Angel Guzman-Perez

Assignees

  • SCORPION THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20231004

Claims (20)

  1. 1 . A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: is each R 1 is independently selected from halogen; m is 0, 1, 2, or 3; R 2 is an unsubstituted C1-C6 alkyl; R 3 is a C1-C6 alkyl, a C1-C6 haloalkyl; Ring A is a pyrimidinyl; R 4 is —NR A R B ; n is 1; and R A and R B are each hydrogen.
  2. 2 . (canceled)
  3. 3 . (canceled)
  4. 4 . The compound of claim 1 , wherein is
  5. 5 . The compound of claim 1 , wherein is
  6. 6 . The compound of claim 1 , wherein is
  7. 7 . The compound of claim 1 , wherein m is 1.
  8. 8 . The compound of claim 1 , wherein m is 2.
  9. 9 . (canceled)
  10. 10 . (canceled)
  11. 11 . The compound of claim 1 , wherein each R 1 is fluoro.
  12. 12 .- 15 . (canceled)
  13. 16 . The compound of claim 1 , wherein m is 0.
  14. 17 . (canceled)
  15. 18 . (canceled)
  16. 19 . The compound of claim 1 , wherein R 2 is methyl.
  17. 20 .- 25 . (canceled)
  18. 26 . The compound of claim 1 , wherein R 3 is a C1-C6 haloalkyl.
  19. 27 . The compound of claim 1 , wherein R 3 is difluoromethyl.
  20. 28 . The compound of claim 1 , wherein R 3 is trifluoromethyl.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/414,173, filed on Oct. 7, 2022, which is incorporated herein by reference in its entirety. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named “50006-0102W01_ST26_SL.XML.” The XML file, created on Oct. 3, 2023, is 2,935 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, and compounds of Formula (II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) PI3Kα activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same. BACKGROUND Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene is a part of the PI3K/AKT/TOR signaling network and is altered in several human cancers. Several investigators have demonstrated the role of PI3K/AKT signaling is involved in physiological and pathophysiological functions that drive tumor progression such as metabolism, cell growth, proliferation, angiogenesis and metastasis. (See, Fruman, D. A. The PI3K Pathway in Human Disease. Cell 2017, 170, 605-635 and Janku, F. et al., Targeting the PI3K pathway in cancer: Are we making headway?Nat. Rev. Clin. Oncol.2018, 15, 273-291.) Suppression (e.g., pharmacological or genetic) of PI3K/AKT/TOR signaling may cause cancer cell death and regression of tumor growth. The PI3K pathway can be activated via, for example, point mutation(s) of the PIK3CA gene or via inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30-50% human cancers and contributes to resistance to various anti-cancer therapies. (See, Martini, M. et al., PI3K/AKT signaling pathway and cancer: An updated review. Ann. Med. 2014, 46, 372-383 and Bauer, T. M. et al., Targeting PI3 kinase in cancer. Pharmacol. Ther. 2015, 146, 53-60.) PI3K consists of three subunits: p85 regulatory subunit, p55 regulatory subunit, andp110 catalytic subunit. According to their different structures and specific substrates, PI3K is divided into 3 classes: classes I, II, and III. Class I PI3Ks include class IA and class IB PI3Ks. Class IA P13K, a heterodimer of p85 regulatory subunit and p110 catalytic subunit, is the type most clearly implicated in human cancer. Class IA PI3K includes p110α, p110β and p110δ catalytic subunits produced from different genes (PIK3CA, PIK3CB and PIK3CD, respectively), while p110γ produced by PIK3CG represents the only catalytic subunit in class IB PI3K. PIK3CA, the gene encoding the p110α subunit, is frequently mutated or amplified in many human cancers, such as breast cancer, colon cancer, gastric cancer, cervical cancer, prostate cancer, and lung cancer. (See, Samuels Y, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304:554.) However, the development of PI3K inhibitors has been problematic for several reasons including (i) adaptive molecular mechanisms upon therapeutic inhibition of PI3K, (ii) inability to specifically inhibit signaling by PIK3CA mutations while sparing endogenous p110α, (iii) the limited use of these therapies in rational combinations, including those informed with strong mechanistic support, and (iv) dose-limiting toxicities that prevent sustained PI3K pathway suppression. (See, Hanker et al., Challenges for the Clinical Development of PI3K Inhibitors: strategies to Improve Their Impact in solid Tumors, Cancer Discovery, April 2019;9: 482-491.) For example, alpelisib is an alpha-selective PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3Kα. However, the therapeutic benefit of alpelisib is limited by wild-type PI3Kα inhibition in normal tissues, resulting in dose-limiting toxicities including hyperglycemia. Additionally, there are other factors and compensatory pathways derived from both clinical and in vitro lab studies, which affect PI3K signaling, such as HRAS and KRAS mutations, which reduce susceptibility to PI3K inhibitors (and knockdown of these has shown to improve sensitivity to PI3K inhibitors). (See, Misrha, R.; PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci. 2021, 22, 3464.) Domain deletions in PIK3CA can activate PI3K signaling significantly and also enhance the sensitivity to PI3K inhibitors. (See, Croessmann, S. et al., Clin. Cancer Res. 2018, 24, 1426-1435.) Thus, target