Substituted pyrrolidones and piperidones as small molecule inhibitors of EZH2 and EED protein binding
Inventors
Assignees
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Publication Number
US-12612361-B2
Publication Date
2026-04-28
Expiration Date
Abstract
Disclosed are substituted pyrrolidones and piperidones which may be utilized as EZH2 targeting agents. The substituted pyrrolidones and piperidones may include substituted 2-pyrrolidones and 2-piperidones. The disclosed pyrrolidones and piperidones may be used in pharmaceutical compositions and methods for treating cell proliferative disorders such as cancer.
Core Innovation
The invention relates to compounds having formula I, including pharmaceutically acceptable salts thereof, and to their use for inhibiting EZH2-related biological activity. It provides methods for inhibiting the growth of cells that express EZH2 in a subject in need thereof and methods of inhibiting binding of the EZH2 protein in the PRC2 complex by administering a compound of formula I.
The formula I structure includes A as —C(R1)(R2)— and X selected from —N(R3)C(O)—, —N(R3)CH2—, —CH2N(R3)C(O)—, —N(R3)C(O)CH2—, —N(R3)—, —N(R3)S(O)(O)—, and —C(O)N(R3)—, where R1, R2, and R3 are independently selected from hydrogen and alkyl. The remaining substituents R and R′ are independently selected from cycloalkyl, heterocycloalkyl, alkyl(heterocycloalkyl), aryl, heteroaryl, alkyl(aryl), and alkyl(heteroaryl), and optionally substituted with alkyl, alkoxy, halogen, haloalkyl, amino, cyano, nitro, aryl, hydroxyl, carboxyl, carboxy(alkyl) ester, acyl, and oxo.
The disclosed embodiments are illustrated by chemical structures showing an EZH2/PRC2-targeted pharmacophore with variable aromatic substitutions, including halogens and fluoroalkyl groups such as CF3, together with hydroxyl groups and heterocyclic amide/lactam-like ring features. Some shown embodiments further include sulfur-containing linkages/functional groups and stereochemical markers, supporting specific formula I compound selections within the stated variable framework.
Claims Coverage
Two independent claims are identified, each covering administration of a formula I compound, or a pharmaceutically acceptable salt, to achieve EZH2-related functional inhibition in a subject. Across the independent claims, the coverage is defined by the same core formula I constraints and differs in the biological target outcome: inhibition of EZH2-expressing cell growth versus inhibition of EZH2 binding in the PRC2 complex.
Inhibiting EZH2-expressing cell growth using formula I compounds
A method of inhibiting the growth of cells that express EZH2 in a subject in need thereof by administering a compound having a formula I, or a pharmaceutically acceptable salt thereof, wherein m is 0-2, n is 0-1, and p is 0-1 with the proviso that (m+n+p) is 2 or 3; A is —C(R1)(R2)—; X is selected from —N(R3)C(O)—, —N(R3)CH2—, —CH2N(R3)C(O)—, —N(R3)C(O)CH2—, —N(R3)—, —N(R3)S(O)(O)—, and —C(O)N(R3)—; R1, R2, and R3 are independently selected from hydrogen and alkyl; and R and R′ are independently selected from cycloalkyl, heterocycloalkyl, alkyl(heterocycloalkyl), aryl, heteroaryl, alkyl(aryl), and alkyl(heteroaryl), with optional substitution patterns as defined.
Inhibiting EZH2 binding in the PRC2 complex using formula I compounds
A method of inhibiting binding of the EZH2 protein in the PRC2 complex in a subject in need thereof by administering a compound having a formula I, or a pharmaceutically acceptable salt thereof, wherein m is 0-2, n is 0-1, and p is 0-1 with the proviso that (m+n+p) is 2 or 3; A is —C(R1)(R2)—; X is selected from —N(R3)C(O)—, —N(R3)CH2—, —CH2N(R3)C(O)—, —N(R3)C(O)CH2—, —N(R3)—, —N(R3)S(O)(O)—, and —C(O)N(R3)—; R1, R2, and R3 are independently selected from hydrogen and alkyl; and R and R′ are independently selected from cycloalkyl, heterocycloalkyl, alkyl(heterocycloalkyl), aryl, heteroaryl, alkyl(aryl), and alkyl(heteroaryl), with optional substitution patterns as defined.
Across the independent claims, the core coverage is directed to administering formula I compounds with defined m/n/p constraints and defined A and X selections, where R1/R2/R3 are hydrogen or alkyl and R/R′ are selected from a defined set of ring or alkyl/aryl classes with optional substituents. Dependent claims further narrow m/n/p values and specify substituent patterns such as hydroxyl and haloalkyl, or hydroxyl and trifluoromethyl, and in at least one instance add a condition of not inhibiting growth of cells that do not express EZH2.
Stated Advantages
Inhibiting the growth of cells that express EZH2.
Inhibiting binding of EZH2 protein in the PRC2 complex.
Selectivity in which the compound does not inhibit growth of cells that do not express EZH2.
Improved efficacy versus existing EZH2 inhibitors through selective EZH2–EED interaction inhibition.
Selective inhibition effect described as reduced impact on EZH2− cells.
Documented Applications
Use in methods for inhibiting growth of cells that express EZH2 in a subject in need thereof.
Use in methods for inhibiting binding of the EZH2 protein in the PRC2 complex in a subject in need thereof.
Pharmaceutical compositions for cancer indications, including use as small-molecule inhibitors targeting EZH2 function in the PRC2 complex.
Inhibition of EZH2+ cell growth.
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