Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • McCarthy, Kathleen • Haney, William
Assignees
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Publication Number
US-11162101-B2
Publication Date
2021-11-02
Expiration Date
Abstract
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, 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 (IV), or pharmaceutically acceptable salts or solvates thereof, having a stereochemical purity of at least 80%. The compounds include ring Q as a 5-6 or 6-5 fused bicyclic heteroaryl optionally substituted with halogen, cyano, amino and substituted amino groups, hydroxyl, carboxylic acid and alkyl ester forms, amide and sulfonamide-related groups, alkyl and cycloalkyl groups, fluoroalkyl and heteroalkyl groups, alkoxy and fluoroalkoxy groups, thioalkyl and sulfinyl/sulfonyl variants, NH(cyclopropyl), OCH3, OCF3, and oxo.
The structure further specifies X as —NR3, each R1 as independently selected from H, D, C1-C6 alkyl, —CD3, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl, and R3 as —OR′, —N(R1)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl. Z is CR7 with R7 being H, W is C1-C4 alkylene, R is H, and R11 through R18 are each independently selected from H, F, OR1, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl, with optional hydroxy, amino, methoxy, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino substitution.
The disclosure also includes small molecule splice modulating compounds that modulate pre-mRNA splicing by altering splice-site/base-pairing and spliceosome component interactions, including modulation of exon skipping/inclusion, pseudoexons, intron inclusion, and NMD. An example is given for tau (MAPT) exon 10 splicing, where modulation affects the 3R/4R isoform ratio and exon 10 inclusion outcomes, and the document also states therapeutic use for diseases associated with splicing modulation.
Claims Coverage
The independent claim set centers on a Formula (IV) compound with a fused bicyclic heteroaryl ring Q, broad optional substitution on ring Q, defined variable groups X, R1, R3, Z, W, R, and R11-R18, and a stereochemical purity requirement of at least 80%. Dependent claims further refine ring Q size and heteroatom content, enumerate ring Q substituents, narrow R3 and W, and include a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient.
Formula (IV) compound with stereochemical purity requirement
A compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, having a stereochemical purity of at least 80%.
5-6 or 6-5 fused bicyclic heteroaryl ring Q with optional substituents
Ring Q is 5-6 or 6-5 fused bicyclic heteroaryl, optionally substituted with one or more substituents selected from halogen, —CN, —NH2, —NH(CH3), —N(CH3)2, —OH, —CO2H, —CO2(C1-C4 alkyl), C(=O)NH2, C(=O)NH(C1-C4 alkyl), C(=O)N(C1-C4 alkyl)2, S(=O)2NH2, S(=O)2NH(C1-C4 alkyl), S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, —SC1-C4 alkyl, —S(=O)C1-C4 alkyl, —S(=O)2(C1-C4 alkyl), —NH(cyclopropyl), —OCH3, —OCF3, and oxo.
Defined X, R1, R3, Z, W, R, and R11-R18 variables
X is —NR3; each R1 is independently selected from H, D, C1-C6 alkyl, —CD3, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl; R3 is —OR′, —N(R1)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C7 heterocycloalkyl; Z is CR7 with R7 being H; W is C1-C4 alkylene; R is H; and R11-R18 are each independently selected from H, F, OR1, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 heteroalkyl, with optional hydroxy, amino, methoxy, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino substitution.
Ring Q refinement to 8-10 ring atoms and 1-3 heteroatoms
In dependent scope, ring Q is an optionally substituted 5-6 or 6-5 fused bicyclic heteroaryl with 8 to 10 ring atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O, or S.
Enumerated ring Q structures with substituent and m constraint
In dependent scope, ring Q is selected from multiple depicted ring structures, where each R is independently chosen from cyano, halogen, hydroxy, C1-C4 alkyl, —OCH3, —OCD3, C1-C4 alkoxy, or C3-6 cycloalkyl, and m is 0, 1, 2, or 3.
Restricted R3 substituent set
In dependent scope, R3 is one of several listed methyl/aryl or substituted methyl groups including —CH3, —CD3, —CF3, and various O-alkyl variants.
Specific W alkylene
In dependent scope, W equals —CH2CH2—.
Pharmaceutical composition
A pharmaceutical composition containing the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier or excipient.
The claims cover a Formula (IV) compound defined by a fused bicyclic heteroaryl ring Q with broad optional substitution, multiple variable group constraints, and a stereochemical purity threshold of at least 80%. Dependent claims further narrow ring Q, restrict R3 and W, and recite a pharmaceutical composition embodiment.
Stated Advantages
The compound has a stereochemical purity of at least 80%.
Documented Applications
Therapeutic use for diseases associated with splicing modulation.
Modulating pre-mRNA splicing, including exon skipping/inclusion, pseudoexons, intron inclusion, and NMD modulation.
Tau (MAPT) exon 10 splicing and modulation of the 3R/4R isoform ratio.
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