Aminothiazole compounds as inhibitors of CTPS1
Inventors
Quddus, Abdul • Novak, Andrew • Cousin, David • CHATZOPOULOU, Elli • BLACKHAM, Emma • Jones, Geraint • Thomas, Jennifer • WRIGGLESWORTH, JOSEPH • Duffy, Lorna • Birch, Louise • George, Pascal • Ahmed, Saleh
Assignees
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Publication Number
US-11655246-B2
Publication Date
2023-05-23
Expiration Date
Abstract
Compounds of formula (I): (I) and related aspects.
Core Innovation
The invention relates to compounds of formula (I), including salts, solvates, and salt and solvate forms, defined by multiple variable substituents and conditional ring-formation relationships. The structure constrains R1, R3-R6, Ar1, Ar2, R10-R13, and R21-R24 to specified chemical classes, with Ar1 as a 6-membered aryl or 6-membered heteroaryl and Ar2 attached to Ar1 in the para position relative to the amide.
The structural definitions further include ring-forming rules in which selected substituent pairs form 5- or 6-membered cycloalkyl or oxygen-containing heterocycloalkyl motifs, together with additional positional constraints such as ortho or meta attachment of R12 relative to Ar1. The claim language also includes an N-oxide (N+-O−) possibility when R12 is linked with a nitrogen atom.
The disclosure also describes thiazole-based and aminothiazole-related small-molecule scaffolds, including thiazol-4-yl/propanamide-sulfonamide derivatives and cyclopropanesulfonamido-thiazole variants, with multiple substituted analogs and intermediate classes. The document presents synthetic and characterization content for numerous example compounds and intermediates, including chromatographic retention times, mass spectrometry, and 1H NMR assignments.
Claims Coverage
The consolidated claim set includes three independent claim types: a compound of formula (I), a second compound of formula (I), and a salt of a compound of formula (I). Across these claims, the inventive scope is defined by constrained substituent classes, fixed aryl attachment relationships, conditional ring-formation rules, and explicit salt/solvate coverage where stated.
Formula (I) compound with constrained substituent classes and ring-formation rules
A compound of formula (I) wherein R1, R3-R6, Ar1, Ar2, R10-R13, and R21-R24 are limited to specified substituent classes, including conditional formation of 5- or 6-membered cycloalkyl or oxygen-containing heterocycloalkyl rings from selected substituent pairs.
Para-position aryl attachment relative to the amide
Ar1 is a 6-membered aryl or 6-membered heteroaryl and Ar2 is a 6-membered aryl or 6-membered heteroaryl attached to Ar1 in the para position relative to the amide.
R12 positional constraint and N-oxide possibility
R12 is attached to Ar2 in the ortho or meta position relative to Ar1, with allowed substituent classes that include the possibility that R12 together with a nitrogen atom forms an N-oxide (N+-O−).
Salt of a formula (I) compound
A salt of a compound of formula (I) is separately claimed, using the same structural constraints and ring-formation relationships as the compound claim.
Overall, the claims center on formula (I) compounds defined by extensive substituent constraints, conditional ring closure, fixed para attachment of Ar2 relative to the amide, and an explicit N-oxide option tied to R12. Separate coverage is provided for the salt form, and salts/solvates are included where stated.
Stated Advantages
Provides drug/substrate tissue distribution use cases for isotopically labeled forms.
Provides metabolic stability use cases for isotopically labeled forms.
Provides in vivo half-life use cases for isotopically labeled forms.
Provides PET studies, including Positron Emission Topography, use cases for isotopically labeled forms.
Provides CTPS1 inhibition for reducing T-cell proliferation and B-cell proliferation.
Certain examples show CTPS1 enzyme inhibitory potency and selectivity over CTPS2.
Documented Applications
Drug/substrate tissue distribution studies using isotopic forms.
Metabolic stability studies using isotopic forms.
In vivo half-life studies using isotopic forms.
PET studies including Positron Emission Topography using isotopic forms.
CTPS1 inhibition in therapeutic methods.
Reduction of T-cell proliferation and B-cell proliferation in a subject.
Treatment of transplant rejection and GVHD.
Treatment of allergy and autoimmune diseases.
Treatment of cancer.
Treatment of psoriasis, lichen planus, restenosis, and neointima, including medical device-coated use.
Inhibiting cytidine triphosphate synthase 1 (CTPS1) to reduce proliferation of immune and cancer cell populations.
Characterization and structural support for multiple synthesized intermediates and compounds using chromatographic and spectroscopic data.
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