Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • Lucas, Brian • Wang, Tiansheng • Feng, Jun
Assignees
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Publication Number
US-11964971-B2
Publication Date
2024-04-23
Expiration Date
Abstract
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, pharmaceutical compositions comprising the same, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.
Core Innovation
The invention relates to compounds of Formula (III), including pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. The compounds are defined by a structural framework in which multiple substituent variables determine the possible chemical forms, including variable groups E, R, R^A, ring Q, X, Z, W, R1, R2, R3, R4, and additional groups R11 through R18. Structural diversity is achieved through the allowed combinations of these variables, including hydrogen, deuterium, fluorine, cyano, and various alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, fluoroalkyl, and heteroalkyl groups.
E is defined as a selected group among —NR—, —O—, —S—, —S(=O)-type, and —S(=O)2-type substituent patterns, with additional options expressed by combinations including —O(=NRE)2-type structures. Ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and is further shaped by enumerated structural constraints in dependent claim sets. X and Z define additional core connectivity elements, with X being selected among a set that includes —O—, —S—, and —NR3—, and Z being C in one configuration or being CR2 in another configuration.
The invention further defines structural variability through other variables and ring systems, including definitions of W as substituted or unsubstituted alkylene or heteroalkylene with specific carbon ranges, and the presence of additional substituent groups selected from hydrogen, deuterium, F, —OR1, alkyl, fluoroalkyl, and heteroalkyl classes. The compound family is constrained by relational selection rules among substituent variables, including positional fluorine and hydrogen relationships and fluorine inclusion conditions, while still maintaining broad formula-based substituent freedom.
Claims Coverage
The consolidated material includes one independent claim directed to a compound of Formula (III) and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. The claim defines the core scaffold and a broad set of substituent variables, while dependent refinements narrow key structural selections such as ring Q substitution patterns, linker W length classes, fluorine positional relationships, and fluorine inclusion requirements. Across the cited claim material, the coverage centers on a Formula (III) compound family with extensive structural variability through defined heteroatom, ring, linker, and substituent options.
Compound of Formula (III) including pharmaceutically acceptable salts or solvates
A compound of Formula (III), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, defined by the stated structural variables and substituent ranges.
Defined linkage heteroatom E and substituent R^E
E is —NR—, —O—, —S—, —S(=O)2—, or —S(=O)(=NRE)—, with R^E selected from hydrogen or substituted or unsubstituted C1–C3 alkyl, C3–C6 cycloalkyl, C2–C5 heterocycloalkyl, C2–C3 alkenyl, or C2–C3 alkynyl; each R^A is independently hydrogen, deuterium, F, —CN, —OR1, —SR1, —S(=O)R1, —S(=O)2R1, or substituted or unsubstituted alkyl, haloalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl.
Ring Q as substituted or unsubstituted aryl or heteroaryl
ring Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, with dependent refinements that further constrain ring Q substitution patterns.
Constrained X and Z relationship
X and Z are defined by alternative structural combinations, including a configuration where Z is C and another where X is —O—, —S—, or —NR3— and Z is CR2, with the bond type selected as a single bond or a double bond as stated in the claim text.
Linker W as substituted or unsubstituted alkylene, heteroalkylene, cycloalkylene, or heterocycloalkylene
W is substituted or unsubstituted C1–C3 alkylene, substituted or unsubstituted C2–C3 alkenylene, substituted or unsubstituted C1–C2 heteroalkylene, substituted or unsubstituted C3–C8 cycloalkylene, or substituted or unsubstituted C2–C7 heterocycloalkylene.
Substituent sets for R, R1, R2, R3, and R4
R is hydrogen or substituted or unsubstituted alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl; each R1 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, —CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, —CD3, or substituted or unsubstituted haloalkyl; R3 is hydrogen, —CN, substituted or unsubstituted C1–C4 alkyl, —CD3, substituted or unsubstituted haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, —C1–C4 alkylene-OR1, substituted or unsubstituted C3–C4 cycloalkyl, or substituted or unsubstituted C2–C3 heterocycloalkyl; and each R4 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, —CD3, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted heteroalkyl.
Substituent constraints for R11 through R18
each R11, R12, R13, R14, R16, and R17 is independently selected from hydrogen, deuterium, F, —OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted heteroalkyl; R15 and R18 are either the same and selected from hydrogen and deuterium, the same and selected from F, —OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl, or not the same and selected from hydrogen, deuterium, F, —OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; a is 0 or 1, b is 0, c is 1, and d is 0 or 1.
Fluorine inclusion condition
At least one of R11 through R18 is or comprises a fluorine.
The claim coverage centers on Formula (III) compounds with an E-linked core, defined ring Q aryl or heteroaryl options, constrained X/Z connectivity, a defined W linker class, broad substituent sets for R and R1 through R4, and explicit fluorine-related selection rules across R11 through R18, including a fluorine inclusion condition and positional fluorine or hydrogen relationships.
Stated Advantages
The invention relates to small-molecule splicing modulator compounds for modulating mRNA splicing of pre-mRNA and thereby treating disease.
The disclosed compounds are intended to modulate splicing activities associated with the spliceosome complex, including alternative splicing of protein-coding genes via exons and introns.
The invention addresses limitations of oligonucleotide therapies, including pharmacokinetics, oral bioavailability, blood-brain barrier penetration, tumor delivery, compartmentalization, and the need for an accessible RNA linear structure.
The small molecules act as splicing modulators that contact cells to modulate splicing at a splice site of pre-mRNA.
Documented Applications
Use as splicing modulators that contact cells to modulate splicing at a splice site of pre-mRNA.
Treating disease.
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