Aminopyrimidine/pyrazine derivatives as CTPS1 inhibitors
Inventors
Quddus, Abdul • BLACKHAM, Emma
Assignees
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Publication Number
US-11987573-B2
Publication Date
2024-05-21
Expiration Date
Abstract
Compounds of formula (I), and related aspects.
Core Innovation
The patent describes a specific compound: 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide, including a salt and/or solvate thereof. The disclosure frames CTPS1 as a target for immunosuppression and anti-cancer therapy, and it states the need for selective CTPS1 inhibitors relative to CTPS2 while reducing T-cell and/or B-cell proliferation.
The core inventive subject matter is an aminopyrimidine/pyrazine derivative inhibitor of formula (I), including related forms, salts/solvates, derivatives, and pharmaceutical embodiments. The disclosure also includes compounds of formula (LVIII) and (IIa), representative compound structures, stereoisomers, and the exact named compound.
The patent further provides synthetic intermediates and routes used to access pyrimidine/pyridine/pyrazine scaffold combinations bearing cyclopropanesulfonamide or sulfonyl groups and tetrahydro-2H-pyran substituents. It discloses Scheme 1 with Suzuki coupling, boronate ester building blocks, protecting-group variants, intermediate-generation methods including decarboxylation of chloro-pyrimidines, alkylation, and sulfonamide formation, together with characterization data for intermediates and compounds.
Claims Coverage
The independent claims cover a single specifically named compound, extend to salts and/or solvates, and include pharmaceutical composition embodiments. Across the inputs, the claim coverage centers on 4 inventive features.
Specific named compound with salt and/or solvate scope
4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide, or a salt and/or solvate thereof.
Pharmaceutically acceptable salt form
The compound in pharmaceutically acceptable salt form.
Pharmaceutical composition including the claimed compound
A pharmaceutical composition including the claimed compound.
Pharmaceutical composition including the specified pharmaceutically acceptable salt
A pharmaceutical composition including the pharmaceutically acceptable salt of the claimed compound.
Overall claim coverage is focused on the specifically named tetrahydro-2H-pyran carboxamide compound, with dependent coverage extending to pharmaceutically acceptable salt form and to pharmaceutical compositions containing either the compound or its pharmaceutically acceptable salt.
Stated Advantages
Selective CTPS1 inhibition relative to CTPS2 is motivated and supported through disclosed potency/selectivity targets.
Reduction of T-cell proliferation.
Reduction of B-cell proliferation.
Treatment and/or prophylaxis of graft rejection and GVHD.
Treatment and/or prophylaxis of allergy and autoimmune diseases.
Treatment of cancer, including hematologic and non-hematologic cancer.
Therapeutic use is disclosed for vascular restenosis/neointima recovery.
The disclosure concludes that tested compounds inhibit CTPS1.
The disclosure concludes at least 2-fold CTPS1 selectivity, often above 60-fold.
Documented Applications
Reducing T- and/or B-cell proliferation in immune disorders, including transplant rejection and GVHD.
Treatment and/or prophylaxis of graft rejection.
Treatment and/or prophylaxis of GVHD.
Treatment and/or prophylaxis of allergy.
Treatment and/or prophylaxis of autoimmune diseases.
Treatment of cancer, including hematologic and non-hematologic cancer.
Treating vascular restenosis/neointima recovery.
CTPS1 enzyme inhibition evaluation using an ADP-Glo™ Max assay, with results grouped by potency range.
CTPS1 versus CTPS2 selectivity assessment using RapidFire/MS with fold-selectivity categories.
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