Polo like kinase 4 inhibitors
Inventors
Ndubaku, Chudi • MOORE, Jared Thomas • GIBBONS, Paul Anthony • Chang, Jae Hyuk • Romero, F. Anthony • Du, Xiaohui • Kawai, Hiroyuki • Ciblat, Stephane • Wang, Hong • Albert, Vincent • Constantineau-Forget, Lea • SILVA, Hugo de Almeida • POLAT, Dilan Emine • NAYYAR, Amit • SHORE, Daniel Gordon Michael • Wu, Kejia • Tan, Joanne
Assignees
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Publication Number
US-11858915-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Disclosed herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, that are inhibitors of Polo Like Kinase 4 (PLK4). Also disclosed herein are pharmaceutical compositions comprising the compounds of Formula (I), or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients. Further disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to compounds defined by Formula (I) and related illustrated chemical structures, including spiro[cyclopropane-1,3′-indol]-2′-one or spiro[cyclopropane-1,3′-indolin]-2′-one scaffolds linked to indazole and heteroaryl fragments. The chemical definitions include extensive variable substituent coverage, stereoisomers, diastereomers, racemic mixtures, pharmaceutically acceptable salts, and solvates.
Representative embodiments include substituted pyrimidine, pyridinyl, pyridazinyl, pyrazolyl, pyrazinyl, pyrrolo[3,2-d]pyrimidin-4-yl, benzofuran, indolinone, and related heterocycle motifs, with substitutions such as morpholine, oxetane, azetidine, azaspiro, thiomorpholine, sulfonamide, sulfonyl, carboxamide, carbonitrile, phosphoryl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, chloro, fluoro, and difluoro groups. The disclosure also provides specific numbered compounds, image-defined structures, and embedded chemical structure images.
The examples include late-stage intermediates and final products accessed through Pd-catalyzed coupling, amination, deprotection, cyclization, and purification, with characterization data including ESI-MS, LCMS, and 1H NMR. The disclosed compounds are associated with biological testing focused on PLK4 inhibition, comparisons against Aurora A and Aurora B, and cancer treatment language, together with biomarker detection concepts involving nucleic acid profiling, ctDNA, ctRNA, qPCR, and sequencing.
Claims Coverage
The consolidated claim coverage centers on one independent compound-selection claim family, with the independent claims covering compounds selected from illustrated chemical structures and their pharmaceutically acceptable salts. Across the inputs, the recurring inventive features are the selected compound group, specific illustrated structures, salt coverage, and a dependent pharmaceutical composition feature.
Selected illustrated compound group
A compound selected from the group consisting of illustrated chemical structures, or a pharmaceutically acceptable salt thereof.
Particular illustrated chemical structure with salt alternative
The compound is specified as a particular chemical structure shown in the images, including a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salt form
A pharmaceutically acceptable salt, or the compound itself, of the compound disclosed in the claim or defined by the provided chemical structure/images.
Pharmaceutical composition with pharmaceutically acceptable excipients
A pharmaceutical composition that includes the compound from claim 1 (or a pharmaceutically acceptable salt of it) together with one or more pharmaceutically acceptable excipients.
Overall, the claims are directed to structural selection from illustrated compound groups, explicit inclusion of pharmaceutically acceptable salt forms, and in one dependent claim a pharmaceutical composition including pharmaceutically acceptable excipients.
Stated Advantages
Many compounds potently inhibit PLK4 with comparatively less inhibition of Aurora A/B, demonstrating enhanced PLK4 selectivity versus CFI-400495.
Inhibiting polo-like kinase 4 (PLK4).
Treating cancer, including solid tumors and hematologic cancers.
Treating cancer by administering a Formula (I) PLK4/SAK inhibitor compound to a subject.
Documented Applications
Biological activity testing for selective inhibition of PLK4 using ADP-Glo Kinase assays, with comparison to Aurora A and Aurora B and cell viability assessment using CellTiter-Glo (CTG) assay in CHP-134 cells.
Methods of treating cancer, including solid tumors and hematologic cancers.
Cancer contexts referenced include neuroblastoma, breast cancer, pancreatic cancer, lung cancer, leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, triple negative breast cancer, prostate cancer, bone cancer, skin cancer, head and neck cancer, melanoma, uterine/ovarian/rectal/anal region/stomach/colon cancer, Hodgkin’s disease, lymphocytic lymphomas, bladder/kidney/ureter, renal cell carcinoma, primary CNS lymphoma, spinal axis tumors, brain stem glioma, and pituitary adenoma.
Biomarker detection and genetic-material profiling concepts including nucleic acid assays, circulating tumor DNA (ctDNA), and circulating tumor RNA (ctRNA).
Pharmaceutical compositions comprising the disclosed compounds and pharmaceutically acceptable excipients.
Cancer treatment and PLK4 inhibition, with patient selection based on PLK4 expression and TRIM37 overexpression/amplification.
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