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EP-4739306-A2 - POLO-LIKE KINASE 1 INHIBITORS

EP4739306A2EP 4739306 A2EP4739306 A2EP 4739306A2EP-4739306-A2

Abstract

The present invention relates to inhibitors of polo-like kinase 1 ("PLK1"). In particular, the present invention relates to compounds that selectively inhibit the activity of PLK1, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor, such as methods for treating PLK1 -mediated diseases and disorders, such as cancer.

Inventors

  • BOBINSKI, Thomas, Paul
  • LEE, Matthew, Randolph

Assignees

  • Cervero Therapeutics, LLC

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. We claim: 1. A compound of Formula (I): wherein: R 1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, cycloalkyl, haloalkyl, or aniline; R 2 is hydrogen, alkoxy, or -O-haloalkyl optionally substituted with one or more alkoxy groups, R 3 is hydrogen, heterocyclyl optionally substituted with one or more R 4 , -NH-L 1 - N(R A R B ), -NH-L 2 -cycloalkyl or -NH-L 2 -heterocyclyl, wherein the cycloalkyl or the heterocyclyl is optionally substituted with one or more R 5 ; R 6 is OCF 3 , SCH 3 , cyclopropane, O-cyclopropane, OCH 3 , CH 2 CH 3 , azetidine, or S(O)(O)CH 3 ; R 7 is NH 2 , NHCH 3 , or CH 3 ; each R 4 is independently C1-C4 alkyl, cyclopropyl, hydroxyalkyl, -L 1 -N(R A R B ), halogen, O, O-CH 3 , NH 2 , -C(O)O-t-butyl; -L 3 -aryl; or -L 4 -heterocyclyl; each R 5 is independently C1-C4 alkyl, N(CH 3 )(CH 3 ), or heterocyclyl optionally substituted with aryl; each L 1 is C1-C4 alkylene; each L 2 is a bond or C1-C4 alkylene; each L 3 is -CH 2 -O-CH 2 -; each L 4 is a bond or methylene; each R A is hydrogen or C1-C3 alkyl; each R B is hydrogen or C1-C3 alkyl; and pharmaceutically acceptable salts thereof.
  2. 2. The compound of claim 1, wherein R 1 is halogen.
  3. 3. The compound of claim 2, wherein the halogen is chlorine, fluorine, or bromine.
  4. 4. The compound of claim 1, wherein R 1 is hydroxy.
  5. 5. The compound of claim 1, wherein R 1 is C1-C6 alkyl.
  6. 6. The compound of claim 5, wherein the C1-C6 is alkyl, is methyl, ethyl, or isopropyl.
  7. 7. The compound of claim 1, wherein R 1 is cycloalkyl.
  8. 8. The compound of claim 7, wherein the cycloalkyl is cyclopropyl.
  9. 9. The compound of claim 1, wherein R 1 is haloalkyl.
  10. 10. The compound of claim 9, wherein the haloalkyl is fluoromethyl, difluoromethyl, or trifluoromethyl.
  11. 11. The compound of claim 1, wherein R 1 is aniline.
  12. 12. The compound of claim 11, wherein the aniline is NH 2 .
  13. 13. The compound of any of claims 1-12, wherein R 2 is alkoxy or -O-haloalkyl.
  14. 14. The compound of claim 13, wherein R 2 is alkoxy.
  15. 15. The compound of claim 14, wherein the alkoxy is methoxy or propoxy.
  16. 16. The compound of claim 13, wherein R 2 is -O-haloalkyl.
  17. 17. The compound of claim 16, wherein the haloalkyl is difluoromethyl.
  18. 18. The compound of any of claims 1-17, wherein R 6 is OCF 3.
  19. 19. The compound of any of claims 1-18, wherein R 7 is NH 2 .
  20. 20. The compound of any of claims 1-19, wherein R 3 is heterocyclyl optionally substituted with one or more R 4 , -NH-L 1 -N(R A R B ), -NH-L 2 -cycloalkyl or -NH-L 2 -heterocyclyl, wherein the cycloalkyl or the heterocyclyl is optionally substituted with one or more R 5 .

Description

POLO-LIKE KINASE 1 INHIBITORS FIELD OF THE INVENTION [0001] The present invention relates to inhibitors of polo-like kinase 1 (“PLK1”). In particular, the present invention relates to compounds that selectively inhibit the activity of PLK1, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor, such as methods for treating PLK1-mediated diseases and disorders, such as cancer. BACKGROUND OF THE INVENTION [0002] TP53 is the most frequently mutated and inactivated gene in cancer, resulting in a decrease in the levels of functional p53. Since existing approaches designed to directly target p53 have shown limited clinical success, there remains a high unmet medical need for new therapeutics to address cancers driven by changes to p53 biology. SUMMARY OF THE INVENTION [0003] Provided are compounds of Formula (I): Formula (I) wherein R1, R2, R3, R6, and R7 are as defined herein, and pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or elixir. [0004] Provided are methods for treating PLK1-mediated diseases or disorders in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. [0005] Also provided herein is a use of a compound of Formula (I), or a pharmaceutically acceptable salt or thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of PLK1. [0006] Also provided herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a PLK1-mediated disease or disorder. DETAILED DESCRIPTION OF THE INVENTION [0007] The present invention relates to inhibitors of polo-like kinase 1 (“PLK1”). In particular, the present invention relates to compounds that covalently inhibit the activity of PLK1, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of use therefor, such as methods for treating plk1-mediated diseases and disorders, such as cancer. PLK1 [0008] Polo-like kinase 1 (PLK1), a member of the polo subfamily of Serine/Threonine protein kinases, is important for a variety of cellular functions, including regulation of cell cycle progression and the DNA damage response (DDR). PLK1 overexpression, which undermines cellular checkpoints, thereby resulting in heightened cell proliferation, has been observed across a large spectrum of human cancers, solid tumors as well as hematologic, and has been found to be associated with poor clinical prognosis as well as resistance to chemotherapy. In contrast, PLK1 depletion or inhibition leads to mitotic arrest and DNA damage, often accompanied by cell death, and enhances the sensitivity of cancer cell viability to irradiation. The important role of PLK1 in cancer is widely accepted as unassailable. [0009] As a component of the DDR, PLK1 plays a role in the oscillatory behavior in the activity of p53, which is a regulatory tumor suppressor protein important for DNA stability and known as the guardian of the genome. The kinase activity of PLK1 promotes proteasomal degradation of p53 through E3 ligases TOPORS and MDM2, with PLK1 depletion or inhibition resulting in elevated cellular levels of p53. In addition, active PLK1 can physically bind and inhibit p53 activity to transactivate the transcription of tumor suppressor genes. Polo-like kinase 3 (PLK3), another member of the polo subfamily of kinases, has an opposing role to PLK1 in p53 activity; PLK3-mediated phosphorylation of p53 increases its transactivation function. [0010] While pan-PLK inhibitors can have off-setting effects on p53 function, PLK1-specific inhibitors, the PLK1-specific inhibitors of the present disclosure, can selectively increase p53 levels and activity. TP53 is found to be mutated in ~50% of human cancers, more than any other gene, and mutations in TP53 are among the most common emergent alterations in refractory cancers (e.g., see Hsiehchen et al., (2022) Nat. Comm.13: 7477). Since no effective p53-based therapeutic has been successfully translated into clinical treatment, the PLK1-specific inhibitors of the present disclosure may be able to lead to therapeutic benefit by raising p53 levels in cancer cells, including but not limited to those that are p53-defective or p53-altered. DEFINITIONS [0011] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with the present disclo