Imidazo[1,2-c]pyrimidine derivatives as PRC2 inhibitors for treating cancer
Inventors
Marx, Matthew Arnold • Ketcham, John Michael • BURNS, Aaron Craig
Assignees
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Publication Number
US-12252493-B2
Publication Date
2025-03-18
Expiration Date
Abstract
Disclosed are compounds that inhibit Polycomb Repressive Complex 2 (PRC2) activity. In particular, disclosed are compounds of Formula (I) and pharmaceutical compositions thereof, and methods of using the compounds and pharmaceutical compositions in, for example, methods of treating cancer.
Core Innovation
The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, including substituted imidazo[1,2-c]pyrimidine compounds and PRC2/EZH2-targeted imidazo[1,2-c]pyrimidine derivatives. The structure is defined by variables including Z, X, R1, R2, R3, R4, L, Y1, Y2, R5a, R5b, R6, R7, R8a, R8b, R9, R10, R11, and n, with Z being O or S and n being 1 or 2. The disclosed examples include fluorinated benzofuran or benzothiophene substituents, deuterated analogs, benzofuran/benzothiophene carbonitrile and methanamine derivatives, and imidazo[1,2-c]pyrimidine cores with variations at the 2- and 8-positions.
The compounds comprise substituted imidazo[1,2-c]pyrimidine derivatives, including EED-binding imidazo[1,2-c]pyrimidine PRC2 inhibitors and substituted analogs. The scaffold includes defined substituent classes for R1, R2, R3, R4, R5a/R5b, R6, R7, R8a/R8b, R9, R10, and R11, together with bond, carbonyl, thioether, sulfoxide, sulfone, and sulfonamide linkage options through Y1 and Y2. The disclosure also includes exemplified imidazo[1,2-c]pyrimidin-5-amine scaffolds and pharmaceutically acceptable salts.
The disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. The compounds are described as PRC2 inhibitor compound frameworks and EED-binding imidazo[1,2-c]pyrimidine scaffolds. Biological evaluation is reported for compounds that inhibit PRC2 enzymatic activity and suppress EZH2-dependent histone H3K27 trimethylation.
Claims Coverage
The consolidated claim coverage centers on a broad independent claim to compounds of Formula (I) or pharmaceutically acceptable salts, defined by multiple interlocking structural variables. The independent claim family consistently centers on the substituted compound framework, the defined heteroatom and linkage options, and the allowed substituent classes across the scaffold, with dependent narrowing of selected variable choices and a pharmaceutical composition embodiment.
Substituted compound of formula (i)
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, defined by Z being O or S; X being O, CR11, CR11OH, or C(R11)2; and the substituent framework comprising R1, R2, R3, R4, L, Y1, Y2, R5a/R5b, R6, R7, R8a/R8b, R9, R10, R11, and n.
R1 as aryl, heteroaryl, cycloalkyl, or heterocyclyl with optional r4 substitution
R1 is aryl, heteroaryl, -L-cycloalkyl, or -L-heterocyclyl, optionally substituted with one or more R4, including listed heteroaryl and heterocycle groups such as pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isooxazolyl, isoindolinyl, naphthridinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl.
R2 substituent and constrained r5a/r5b environment
R2 is —C(R5aR5b)R7 or heteroaryl, each R3 is independently C1-C3 alkyl or halogen, and R5a and R5b are each independently hydrogen, C1-C3 alkyl, haloalkyl, cycloalkyl, or aryl, with at least one of R5a or R5b being hydrogen.
Linker and heteroatom-containing attachment groups
L is a bond or C1-C4 alkylene; Y1 is a bond, —C(O)—, or —NHC(O)—; and Y2 is a bond, —S—, —SO—, —SO2—, or —NR10SO2—.
Heterocyclyl-forming r7 and r8a/r8b options
R7 is —NR8aR8b where R8a and R8b together with the nitrogen atom form a 4-8 membered saturated or partially saturated heterocyclyl optionally containing O, N, or S and optionally substituted with R10, or R7 is —OR8a or —NHR8a with R8a selected from hydrogen, C1-C3 alkyl, cycloalkyl, aralkyl, or halosulfonylalkyl.
Optional substitution through r9, r10, and r11 with n limited
Each R9 is independently selected from oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, or —Y1-heterocyclyl; each R10 is independently selected from oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl; each R11 is independently hydrogen or C1-C3 alkyl; and n is 1 or 2.
Pharmaceutical composition including excipient
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, carrier, or diluent.
The claim coverage is dominated by the Formula (I) scaffold and its defined substituent-variable constraints, with dependent narrowing of specific variable choices and a pharmaceutical composition embodiment. The inventive features are expressed through the substitution pattern, linker and ring-formation options, and permitted substituent classes.
Stated Advantages
Improved potency and oral activity and efficacy.
Inhibition of PRC2 enzymatic activity.
Suppression of EZH2-dependent H3K27 trimethylation.
Suppression of cell growth in EZH2-mutant DLBCL cell lines.
Documented Applications
Inhibiting PRC2 activity and inhibiting cell proliferation, and treating PRC2-associated cancers.
Use in pharmaceutical compositions for treating PRC2-associated diseases/disorders.
Use in inhibition of PRC2 enzymatic activity assays and suppression of EZH2-dependent H3K27 trimethylation, including evaluation in EZH2 A677G (Pfeiffer) and EZH2 Y641N (Karpas 422) cell lines.
Assessment of suppression of cell growth in EZH2-mutant DLBCL cell lines using example-dependent IC50 values.
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