Benzothiazole derivatives as DYRK1 inhibitors
Inventors
Svendsen, John Sigurd • Stensen, Wenche • Porter, Roderick Alan
Assignees
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Publication Number
US-10927106-B2
Publication Date
2021-02-23
Expiration Date
Abstract
The present invention relates to compounds of Formula (I), which are DYRK1A and/or DYRK1B inhibitors, and their use in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), metabolic disorders such as Metabolic Syndrome or diabetes mellitus, and cancer.
Core Innovation
The invention concerns substituted heteroaromatic compounds defined by Formula (I), including compounds and pharmaceutically acceptable salts, hydrates, solvates or tautomers. Formula (I) specifies substituent choices for R1, R2, R3, and an aromatic heterocyclic group X that is substituted with a first substituent R4 and optionally a second substituent R5.
X is a five- or six-membered aromatic heterocyclic group containing only one nitrogen atom in the ring, and R4 and R5, if present, are attached to a carbon atom in the heterocyclic group. R4 and R5 are each represented by Formula (II), with covalent bonds V-W, W-Y, and Y-Z restricted to single, double or triple bonds and with defined atom identities and substitution options for V, W, Y, and Z.
The Formula (I) scaffold further constrains R1 and R1a so that R1 and R1a may together form a 5- or 6-membered unsubstituted ring, optionally containing a heteroatom selected from N, O or S. Additional conditions govern cases where W, Y and Z are absent from R4 and R5, and R5, if present, comprises six or fewer non-hydrogen atoms.
Claims Coverage
The independent claim is directed to a compound of Formula (I) with multiple interdependent structural constraints, including the composition of X, the permitted nature of R1/R1a and R2/R3, and the detailed linkage architecture for R4/R5 via Formula (II). The provided claim set also includes dependent coverage that narrows specific substituent definitions and refines therapeutic-use coverage tied to DYRK1A/DYRK1B.
Defined compound of Formula (I) with constrained substituents R1/R2/R3
A compound of Formula (I) wherein R1 is selected from fluorine, an OR2 group, a CONHR3 group, CH2C(O)NHR3, or —C≡CR2; R2 is hydrogen or a C1-3 alkyl group; R3 is hydrogen or a C1-3 alkyl group; and R1a is H, or R1 and R1a together form a 5- or 6-membered unsubstituted ring, optionally containing a heteroatom selected from N, O or S.
Heteroaromatic group X with one ring nitrogen and R4/R5 substitution
X is a five- or six-membered aromatic heterocyclic group containing only one nitrogen atom in the ring, substituted with a first substituent R4 and optionally a second substituent R5, wherein R4 and R5, if present, are attached to a carbon atom in the heterocyclic group.
R4/R5 as Formula (II) with V-W-Y-Z bond and atom constraints
R4 and R5, which may be the same or different, are each a group represented by Formula (II) in which the covalent bonds V-W, W-Y, and Y-Z are single, double or triple bonds, with V representing C, N or F; W representing C, N, O, S, or is absent; Y representing C, N, O, S, or is absent; and Z representing C, N, O, or is absent, with defined substitution options.
Exclusion and size constraints on R4/R5 substituent frameworks
The claim includes the condition that where W, Y and Z are absent from R4 and R5 is also absent, V is not unsubstituted N or C; and where R5, if present, comprises six or fewer non-hydrogen atoms. The claim also covers pharmaceutically acceptable salt, hydrate, solvate or tautomer forms, while excluding certain compounds.
Therapeutic treatment via administration for DYRK1A/DYRK1B-related diseases
A method of treating Alzheimer’s disease or Parkinson’s disease associated with abnormal activity of DYRK1A and/or DYRK1B by administering a therapeutically effective amount of a compound of formula (I) to a subject.
Across the provided independent-claim coverage, the main inventive structure is a compound of Formula (I) defined by interlocking substituent constraints for R1/R2/R3, a one-nitrogen aromatic heterocycle X substituted with R4 and optionally R5, and an R4/R5 linkage architecture governed by Formula (II) with explicit allowed bond types and atom/substitution definitions. The provided dependent coverage also specifies disease-treatment use tied to abnormal activity of DYRK1A and/or DYRK1B for Alzheimer’s disease and Parkinson’s disease.
Stated Advantages
Some compounds inhibit DYRK1A specifically to a greater extent than most other kinases.
The DYRK1A selectivity is attributed to a tight fit of the benzothiazole plus X within the DYRK1A ATP binding pocket.
Documented Applications
Treating Alzheimer’s disease associated with abnormal activity of DYRK1A and/or DYRK1B by administering a therapeutically effective amount of a compound of Formula (I).
Treating Parkinson’s disease associated with abnormal activity of DYRK1A and/or DYRK1B by administering a therapeutically effective amount of a compound of Formula (I).
Therapeutic treatment (and prevention) of Alzheimer’s disease, including in Down syndrome patients, by inhibiting DYRK1A activity and associated tau phosphorylation.
Therapeutic treatment (and prevention) of Parkinson’s disease, including conditions discussed as postencephalitic parkinsonism, by inhibiting DYRK1A activity and associated tau phosphorylation.
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