Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • Lucas, Brian • HORNE, Daniel Brian • Wang, Tiansheng
Assignees
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Publication Number
US-11845744-B2
Publication Date
2023-12-19
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 a method of treating or ameliorating Huntington's disease in a subject by administering a compound of Formula (Id) or Formula (IId), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. The compounds are defined through variable-dependent structural features including X, E, ring Q, W, and multiple substituent groups denoted by R and R1 through R18. The scaffold is further characterized by substituent options that include hydrogen, deuterium, fluorine, and a range of allowed alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl substituents.
In Formula (Id), X is selected from —NR3—, —O—, or —S—, and in Formula (IId), X is defined such that E is —NR. Ring Q is defined as ortho hydroxy substituted aryl or ortho-hydroxy substituted bicyclic heteroaryl, with optional further substitution. W is limited to substituted or unsubstituted C2–C3 alkylene or substituted or unsubstituted C2–C3 alkenylene, and the substituent framework includes R, each R1, R2, R3, each R4, R15, R16, R17, and R18 within specified identity ranges.
The disclosure also describes stereochemically defined compound examples within the disclosed scaffold, including fluorinated and deuterated variants and heteroaryl or heterocyclic ring systems. The compounds are presented as pharmaceutical agents intended for treating or ameliorating Huntington's disease, with examples illustrating substituted compounds that share the same Huntington's disease therapeutic scaffold and the same formula-based structural constraints.
Claims Coverage
The independent claim coverage centers on a method of treating or ameliorating Huntington's disease by administering compounds of Formula (Id) or Formula (IId), including pharmaceutically acceptable salts and solvates. The inventive scope is defined by the scaffold variables X/E, ring Q, W, and multiple substituent positions, with the merged inventive features reflected across the provided claim sets.
Treating Huntington's disease by administering Formula (Id) or Formula (IId) compounds
A method of treating or ameliorating Huntington's disease in a subject comprising administering to the subject a compound of Formula (Id) or Formula (IId), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.
Formula (Id) and Formula (IId) scaffold definitions for X and E
In Formula (Id), X is —NR3—, —O—, or —S—; and in Formula (IId), X is E where E is —NR.
Ring Q as ortho hydroxy substituted aryl or bicyclic heteroaryl
Ring Q is ortho hydroxy substituted aryl or ortho-hydroxy substituted bicyclic heteroaryl, wherein the aryl or bicyclic heteroaryl is optionally further substituted.
W defined as C2–C3 alkylene or C2–C3 alkenylene
W is substituted or unsubstituted C2–C3 alkylene, or substituted or unsubstituted C2–C3 alkenylene.
Substituent scope for R and each R1
R is hydrogen, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, or substituted or unsubstituted C2–C5 heterocycloalkyl; each R1 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, —CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, substituted or unsubstituted C3–C6 cycloalkyl, substituted or unsubstituted C2–C5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Substituent scope for R2 and R3
R2 is hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, —CD3, or substituted or unsubstituted C1–C4 haloalkyl; and R3 is hydrogen, —CN, substituted or unsubstituted C1–C4 alkyl, —CD3, substituted or unsubstituted C1–C4 haloalkyl, substituted or unsubstituted C1–C4 heteroalkyl, or —C1–C4 alkylene-OR1.
Substituent scope for each R4
Each R4 is independently hydrogen, deuterium, substituted or unsubstituted C1–C4 alkyl, —CD3, substituted or unsubstituted C1–C4 haloalkyl, or substituted or unsubstituted C1–C4 heteroalkyl.
Substituent choices for R15, R16, R17, and R18
R16 and R17 are each independently selected from hydrogen, deuterium, F, —OR1, substituted or unsubstituted C1–C4 alkyl, substituted or unsubstituted C1–C4 fluoroalkyl, and substituted or unsubstituted C1–C4 heteroalkyl; and R15 and R18 are each independently selected from the same set.
Optional ring Q substitution count
Ring Q is optionally further substituted with 1, 2, 3, 4, or 5 substituents RB, where each RB is independently selected from the listed substituent groups.
Overall claim coverage centers on a Huntington's disease treatment method defined by administration of Formula (Id) or Formula (IId) compounds. The main inventive features are the scaffold definitions for X/E, ring Q, and W, together with the constrained substituent sets for R, R1, R2, R3, R4, and R15/R16/R17/R18, plus optional ring Q substitution count.
Stated Advantages
Treating or ameliorating Huntington's disease in a subject.
Reducing severity.
Delaying progression.
Inhibiting progression.
Increasing survival.
Documented Applications
Method of treating or ameliorating Huntington's disease in a subject by administering a compound of Formula (Id) or Formula (IId), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.
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