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-12312339-B2
Publication Date
2025-05-27
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 of Formula (I), or pharmaceutically acceptable salts thereof, with Ring A selected from C6-C10 aryl, heteroaryl, C3-C10 cycloalkyl, or heterocycloalkyl. The structural definitions provide extensive variable substituent options for R1, R1a, R1b, R2, R3, R4a, R4b, R4c, R5, R6, R7, and R8a-R8d, including deuterium, halogen, cyano, oxo, nitro, hydroxyl, alkoxy, carbonyl-containing groups, sulfonyl and sulfonamide groups, and phosphonate or phosphoryl-related groups. The parameter n is defined as 0, 1, 2, 3, 4, 5, 6, 7, or 8, and the substituent framework allows optional substitution and, in some cases, pairs of substituents taken together to form an oxo or a heterocycloalkyl.
The examples describe stereochemically defined spiro[cyclopropane-1,3′-indol]-2′-one, spiro[cyclopropane-1,3′-indoline], and related indazole-linked compounds with substituted pyrimidinyl, pyrazinyl, pyridinyl, pyrazolyl, and pyridazinyl side chains. The disclosed compounds vary heteroaryl substituents such as morpholine, piperidine, piperazine, azetidine, oxazepane, hydroxyethoxy, cyclopropyl, difluoro, and trifluoromethyl-containing groups, while maintaining the same core scaffold. The examples are supported by reported mass spectrometry and 1H NMR characterization, and some embodiments are described with absolute configurations such as (1R,2S) and (1S,2R).
Claims Coverage
The provided claim coverage centers on a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one broad independent claim and dependent refinements. Across the merged claim content, the independent scope is defined by Ring A selection, the n parameter, and extensive substituent-variable definitions for the remaining R groups.
Formula (I) compound with Ring A selection
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C6-C10 aryl, heteroaryl, C3-C10 cycloalkyl, or heterocycloalkyl.
Extensive substituent-variable framework
Each R1 is independently selected from deuterium, halogen, cyano, oxo, nitro, hydroxyl, alkoxy, carbonyl-containing groups, thio and sulfonyl-related groups, amide- and amine-related groups, and phosphorus-containing groups, with parallel definitions for R1a and R1b and optional substitution rules including two substituents taken together to form an oxo.
Defined parameter n and restricted R2/R3 values
The parameter n is 0 through 8, and R2 and R3 are each hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl.
Additional position variables R4a-R8d
R4a, R4b, R4c, R5, R6, R7, and R8a-R8d are independently defined by enumerated hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, alkoxy, carbonyl, sulfonyl, amino, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, aryl, and heteroaryl options.
Dependent refinements to Ring A and selected substituents
Dependent claim content narrows Ring A to C6-C10 aryl or heteroaryl, constrains n to 1, 2, or 3, sets each R6 substituent to hydrogen, and sets R8c to OCH3.
Method of treating cancer
A method for treating cancer in a subject by administering a therapeutically effective amount of a compound of Formula (I), where the cancer is neuroblastoma or breast cancer.
Overall, the claim coverage is directed to Formula (I) compounds with broad but explicitly defined Ring A and substituent-variable scope, together with dependent narrowing of Ring A, n, R6, and R8c, and a treatment method limited to neuroblastoma or breast cancer.
Stated Advantages
Documented Applications
A method for treating cancer in a subject by administering a therapeutically effective amount of a compound of Formula (I), where the cancer is neuroblastoma or breast cancer.
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