Methods and compositions for modulating splicing
Inventors
Luzzio, Michael • McCarthy, Kathleen • Haney, William
Assignees
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Publication Number
US-11603531-B1
Publication Date
2023-03-14
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 (I), or pharmaceutically acceptable salts thereof, in which ring Q is monocyclic heteroaryl or fused bicyclic heteroaryl and is optionally substituted. The scaffold includes X as —NR3—, with R3 selected from —OR1, —N(R1)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, or C3-C8 cycloalkyl, and ring G defined by a formula in which Z is CR7. The compounds further define R1, R7, R11 through R17, and combination rules that allow selected pairs to form a C1-3 alkylene group, a bond, or a spirocyclic C3-8 cycloalkyl.
Ring G includes ring-closure rules in which R3 and R7, or in some embodiments R3 and R16, taken together with the intervening atoms form a 4-, 5-, or 6-membered ring. The structural framework also sets R as H and a, b, and c each independently selected from 0, 1, and 2, with R11 through R17 independently selected from H, F, OR1, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, and substituted or unsubstituted C1-C6 heteroalkyl, with further optional hydroxy, amino, methoxy, and mono- or di-C1-C6 alkylamino features. The disclosure presents named ring Q embodiments including indazole, indole, benzothiophene, and benzothiazole, together with additional heteroaryl and heterocycle-containing options.
The examples and further description provide substituted pyridazinyl-linked bicyclic-amino compounds, including 8-azabicyclo[3.2.1]octane derivatives and related oxa-aza bicyclic substituents, as well as phenyl, pyrazolyl-aryl, fluoro, methoxy, hydroxy, and deuterated methoxy variants. The document also includes stereoisomers, prodrugs, isotopically labeled compounds, and pharmaceutically acceptable salts, while emphasizing modular selection rules for the scaffold variables and specific structure-defining examples mapped to the Formula (I) framework.
Claims Coverage
The consolidated claim coverage includes independent claims directed to compounds of Formula (I) or pharmaceutically acceptable salts thereof. Across the claims, the main inventive features are ring Q, X as —NR3—, and ring G defined by Z=CR7 with ring-closure constraints, together with defined substituent rules for R1 and R11-R17; some claims further narrow ring Q to specific named heteroaryl systems.
Formula (I) scaffold with ring Q and —NR3— substituent
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ring Q is monocyclic heteroaryl or fused bicyclic heteroaryl, optionally substituted; X is —NR3—; R3 is selected from —OR1, —N(R1)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, or C3-C8 cycloalkyl; and each R1 is independently selected from H, D, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C7 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Ring G defined by Z=CR7 with 4-, 5-, or 6-membered ring formation
Ring G is a group of a further Formula wherein Z is CR7; R7 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, H, D, or —CH2OR1; and R3 and R7, or in some embodiments R3 and R16, taken together with the intervening atoms form a 4-, 5-, or 6-membered ring.
Substituent set R11-R17 with combination rules
R11, R12, R13, R14, R15, R16, and R17 are each independently selected from H, F, OR1, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, and substituted or unsubstituted C1-C6 heteroalkyl, with optional hydroxy, amino, methoxy, mono-C1-C6 alkylamino, and di-C1-C6 alkylamino features, and selected pairs can form a substituted or unsubstituted C1-3 alkylene group, a bond, or a spirocyclic C3-8 cycloalkyl.
Ring Q limited to named heteroaryl options
Ring Q is indazole, indole, benzothiophene, or benzothiazole, each substituted with 1 or 2 substituents selected from halogen and 5 or 6 membered heteroaryl, or ring Q is selected from an option set of optionally substituted 5 or 6 membered heterocycle-containing choices.
Pharmaceutical composition containing the compound
A pharmaceutical composition containing a compound according to the claim set together with a pharmaceutically acceptable carrier or excipient.
Across the independent claims, the coverage is directed to Formula (I) compounds or pharmaceutically acceptable salts defined by ring Q, an —NR3— substituent, and ring G with Z=CR7 and explicit ring-closure size rules. Additional claim scope is controlled by the R1 and R11-R17 substituent options and pairing rules, with some claims further narrowing ring Q to named heteroaryl systems.
Stated Advantages
Restores RNA isoform and/or protein isoform associated with aberrant pre-mRNA splicing.
Supports modulation of pre-mRNA splicing at specific splice-site sequence motifs.
Provides approaches for treatment, prophylaxis, and delay of progression for cancer and non-cancer diseases or conditions.
Documented Applications
Small molecule splicing modulator (SMSM) use in modulating pre-mRNA splicing.
Modulation of splicing in cells by targeting pre-mRNA and bulged or mutated splice sequences.
Treatment, prophylaxis, and delay of progression for cancer.
Treatment, prophylaxis, and delay of progression for non-cancer diseases or conditions.
Therapeutic treatment contexts including spinal muscular atrophy, DMD, and tumor treatment.
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