Compounds and methods for treating disease
Inventors
Romero, Donna L. • Saunders, Oliver • BISACCHI, Gregory Stuart • Zaller, Dennis • Kapeller-Libermann, Rosana
Assignees
Medchem Consulting LLC • Skylark Bioscience Inc • Rome Therapeutics Inc
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Publication Number
US-12187758-B2
Publication Date
2025-01-07
Expiration Date
Abstract
The invention provides compounds, compositions and methods for treating medical disorders, such as cancer, an autoimmune disorder, and/or a neurological disorder, and inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase using a compound according to Formula I or a pharmaceutically acceptable salt thereof, or a related compound provided herein.
Core Innovation
The invention relates to compounds represented by Formula II and pharmaceutically acceptable salts thereof, including a related variant represented by Formula II-A. The compound definitions constrain R1 and R4 as independently —C(O)R5 or hydrogen, with at least one of R1 and R4 being —C(O)R5, and further define R2 as halo, R3 as halomethyl optionally with deuterium substitution, R5 as C1-20 aliphatic, phenyl, —CH2-phenyl, or hydrogen, R8 as halo, R10 as independently C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, or halo, and m as 0, 1, or 2.
The disclosure provides stereodefined fluorinated oxolane- and pyrimidinone-related scaffold embodiments, including fluorinated pyrimidinedione/pyrimidinone and related heteroaromatic scaffold language. It also includes specific depicted compound embodiments and numbered examples, including compound 67 and other numbered compounds shown in chemical structure images.
The invention further relates to pharmaceutical composition embodiments comprising the compound and a carrier, excipient, and/or vehicle. The disclosed compounds are linked to methods that inhibit LINE1 reverse transcriptase activity and methods for treating selected autoimmune disorders by administering a therapeutically effective amount of the disclosed compounds or pharmaceutically acceptable salts thereof.
The disclosed subject-selection language includes elevated LINE1 RNA expression, elevated LINE1 ORF1 and LINE1 ORF2 polypeptide levels, and/or elevated LINE1 reverse transcriptase activity. The broader disclosure context also references cancer and neurological disorders, inflammatory tissues with a pathogenic type I interferon response, and downstream interferon/ISG responses.
Claims Coverage
The consolidated claim coverage centers on one Formula II compound scaffold and a Formula II-A variant, together with selected depicted compound embodiments, pharmaceutical compositions, and method claims directed to LINE1 reverse transcriptase inhibition and treatment of selected autoimmune disorders. Across the provided claim material, the independent inventive features are the constrained Formula II scaffold and its use-linked therapeutic scope.
Formula II compound scaffold with constrained substituents
A compound represented by Formula II, or a pharmaceutically acceptable salt thereof, wherein R1 and R4 are independently —C(O)R5 or hydrogen, with at least one of R1 and R4 being —C(O)R5; R2 is halo; R3 is halomethyl optionally having one or more hydrogen replaced with deuterium; R5 is independently C1-20 aliphatic, phenyl, —CH2-phenyl, or hydrogen; R8 is halo; R10 is independently C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, or halo; and m is 0, 1, or 2.
Formula II-A compound variant
A compound of Formula II-A, or a pharmaceutically acceptable salt thereof, with specified substituent constraints for R1, R3, R4, R5, R8, R10, and m under the same structural constraints.
Selected depicted compound embodiments
A compound selected from depicted or enumerated options, including specifically identified compound 67 and other numbered compound embodiments shown in the provided chemical structure images, each with pharmaceutically acceptable salt options.
Pharmaceutical composition with carrier, excipient, and/or vehicle
A pharmaceutical composition including a compound of the claimed scaffold or selected compound, together with a carrier, excipient, and/or vehicle.
Inhibiting LINE1 reverse transcriptase activity
A method of inhibiting LINE1 reverse transcriptase activity in a subject by contacting LINE1 reverse transcriptase with an effective amount of a compound selected from the claimed compounds, including compound 67, or a pharmaceutically acceptable salt thereof.
Treating selected autoimmune disorders by administration
A method for treating a selected autoimmune disorder in a subject by administering a therapeutically effective amount of a compound selected from the claimed compounds, including compound 67, or a pharmaceutically acceptable salt thereof, with subject selection based on elevated LINE1 RNA expression and/or elevated LINE1 ORF1 and LINE1 ORF2 polypeptide levels and/or elevated LINE1 reverse transcriptase activity.
Overall, the claims center on a structurally defined Formula II/Formula II-A compound family with constrained substituents and related depicted embodiments, together with composition claims and use claims directed to LINE1 reverse transcriptase inhibition and treatment of selected autoimmune disorders.
Stated Advantages
Inhibiting LINE1 reverse transcriptase activity.
Treating selected autoimmune disorders.
Selecting subjects with elevated LINE1 RNA expression and/or elevated LINE1 ORF1 and LINE1 ORF2 polypeptide levels and/or elevated LINE1 reverse transcriptase activity.
Potent reverse transcriptase inhibition with selectivity versus DNA polymerases (α, β, γ).
Avoid mitotoxicity.
Provide a high therapeutic index.
Inhibit a pathogenic type I interferon response in inflammatory tissues.
Documented Applications
A method for inhibiting LINE1 reverse transcriptase activity in a subject by contacting LINE1 reverse transcriptase with an effective amount of a compound selected from the claimed Formula II compounds, compound 67, or a pharmaceutically acceptable salt thereof.
A method for treating a selected autoimmune disorder in a subject by administering a therapeutically effective amount of a compound selected from the claimed Formula II compounds, compound 67, or a pharmaceutically acceptable salt thereof.
Selected autoimmune disorders including systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Aicardi-Goutieres syndrome, rheumatoid arthritis, psoriasis, graft versus host disease, scleroderma, type I diabetes, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, vasculitis, Sjögren’s syndrome, multiple sclerosis, Parkinson’s disease, Huntington’s disease, peripheral neuropathy, age-related macular degeneration, frontotemporal dementia, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, and major depression.
Patient selection using elevated LINE1 RNA expression and/or elevated LINE1 ORF1 and LINE1 ORF2 polypeptide levels and/or elevated LINE1 reverse transcriptase activity.
Treating cancer, autoimmune disorders, and neurological disorders by inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase.
Applications involving inflammatory tissues with a pathogenic type I interferon response and downstream interferon/ISG responses.
Providing pharmaceutical compositions comprising a claimed compound together with a carrier, excipient, and/or vehicle.
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