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Publication Number
US-11530207-B2
Publication Date
2022-12-20
Expiration Date
Abstract
Described herein are splice modifying compounds affecting splicing of mRNA, such as pre-mRNA, expressed from the FOXM1 gene, compositions comprising thereof, and methods using the same.
Core Innovation
The disclosure is directed to compounds of Formula (II) and pharmaceutically acceptable salts thereof. The compounds are defined by a core structure in which multiple variable groups, including R, R1-R7, R11-R18, and ring or position indices a-f, n, e, and f, take broad sets of substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl options, with specified substituent sets including D, halogen, and related functional groups.
The structural definition further specifies conditions for X, Y, and Z, including X being absent or -NR7-, Y being NR or CR5R6, and Z being N or CR6, together with ring-closure cases that define monocyclic 4, 5, or 6-membered rings. The heterocycloalkyl and heteroaryl portions are limited in ring size and heteroatom content, and the heteroalkyl portions include skeletal atoms selected from O, N, and S and attach at carbon or heteroatom of the heteroalkyl.
The disclosure also includes exemplary small-molecule structures showing an (E)-acrylamide/ene/sulfanone motif combined with a substituted pyridazinyl core. The examples further specify linkage to azabicyclo and oxa/azabicyclo frameworks, a hydroxyphenyl ring, variations in azabicyclic ring size, heteroatom replacements, and amide N-substitution, with additional aryl substituents such as fluorine and sulfonyl-containing vinyl or ene motifs.
The overall inventive focus is the structural definition of SMSM compounds of Formula (II) suitable for FOXM1 gene splicing modulation. The document provides splicing context related to FOXM1 gene splicing modulation, including FOXM1 splice variants (FOXM1A/FOXM1B/FOXM1C) and FOXM1_A2 and FOXM1_BC.
Claims Coverage
The provided claim set includes one explicitly provided independent claim directed to a compound of Formula (II) and pharmaceutically acceptable salts. The inventive features are the structural scope of Formula (II), the allowable substituent classes and indices, and the linkage and ring-closure rules for X, Y, and Z.
Formula (II) compound
A compound of Formula (II), or a pharmaceutically acceptable salt thereof, defined by substituent variables R, R1-R7, R11-R18, and indices a-f, n, e, and f, with each variable selected according to the stated substitution sets and structural constraints.
X, Y, and Z ring-closure structural rules
X is absent or -NR7-, Y is NR or CR5R6, and Z is N or CR6, including cases in which ring formation occurs to give a monocyclic 4, 5, or 6-membered ring under specified conditions.
Heterocycloalkyl and heteroaryl compositional limitations
Heterocycloalkyl groups are monocyclic or bicyclic and contain 1-34 N atoms, 0-2 O atoms, 0-2 P atoms, and 0-1 S atoms in the ring, and heteroaryl groups are 5- or 6-membered monocyclic heteroaryl containing 1-34 N atoms, 0-1 O atoms, and 0-1 S atoms, with heteroalkyl groups containing skeletal atoms selected from O, N, and S.
Pharmaceutical combination with therapeutically active co-agents
A pharmaceutical combination comprising a therapeutically effective amount of the compound of the preceding claim, or a pharmaceutically acceptable salt, together with one or more therapeutically active co-agents.
Across the available independent-definition scope, the coverage centers on Formula (II) compound structures with constrained substitution patterns, controlled X/Y/Z structural linkages and ring-closure options, compositional limitations for heterocycloalkyl and heteroaryl fragments, and a pharmaceutical combination context with therapeutically active co-agents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
FOXM1 gene splicing modulation using splice modifying small-molecule (SMSM) compounds.
Measurement of FOXM1 splice variants FOXM1_A2 and FOXM1_BC using qPCR/RT-qPCR.
Cell viability/proliferation assessment using a proliferation readout with reported IC50-style proliferation values.
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