Aza-heterocyclyl carboxamide and related compounds and their use in treating medical conditions
Inventors
Ryan, Michael Dominic • Pallin, Thomas David • Blench, Toby Jonathan • Mullins, Toby Matthew Grover • Clark, David Edward • Gancia, Emanuela • Ahmad, Nadia Mamoona
Assignees
Charles River Discovery Research Services UK Ltd • X Biotix Therapeutics Inc • Charles River Laboratories Inc
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Publication Number
US-12227475-B2
Publication Date
2025-02-18
Expiration Date
Abstract
The invention provides aza-heterocyclyl carboxamide and related compounds, pharmaceutical compositions, and their use in the treatment of medical conditions, such as bacterial infections, and in inhibiting LpxC activity.
Core Innovation
The invention relates to compounds represented by Formula I, Formula I-A, or pharmaceutically acceptable salts thereof. The compounds are defined by a constrained scaffold in which A1 is a 6-10 membered arylene or 5-10 membered heterocyclylene, A2 is a 4-10 membered aza heterocyclylene with a 4-6 membered saturated aza-heterocyclylene, and A3 is selected from specified aza-heterocyclyl or cycloalkyl options. The variable group X defines linkage forms involving C(O)N(R3)(C0-6 alkylene) or (C0-6 alkylene)-N(R3)C(O), with a bond to A2, and RA, including Y1, and R1, R2, R3, R4, R5, R6, and R7 are restricted to specified ring-size and functional-group sets.
The disclosure further encompasses specific embodiments and representative chemical structures, including compounds listed in Tables 1, 2, and 3-A and examples such as compounds I-1 through I-17, 9A through 9X, and V-9 through V-45. The document includes stereoisomeric compounds and structural depictions showing a consistent bicyclic or heterobicyclic peptidomimetic or aza-heterocyclyl carboxamide scaffold with fluorinated substituents, heteroaryl substituents, hydroxyl groups, and nitrile occurrences.
The compounds are framed as antibacterial agents and LpxC inhibitors. The disclosure states that the compounds inhibit LpxC activity by exposing LpxC to an effective amount of a compound according to Formula I and also includes methods of treating a bacterial infection in a patient by administering a therapeutically effective amount of the compound.
Claims Coverage
The consolidated claim coverage includes two independent claim categories: a Formula I compound claim and explicit table-selection coverage. In total, the independent claim coverage centers on two inventive features: a constrained Formula I structural scaffold and selection of compounds listed in Tables 1, 2, or 3-A.
Formula I compound scaffold
A compound represented by Formula I, Formula I-A, or a pharmaceutically acceptable salt thereof, wherein A1 is a 6-10 membered arylene or 5-10 membered heterocyclylene; A2 is a 4-10 membered aza heterocyclylene with a 4-6 membered saturated aza-heterocyclylene; A3 is selected from specified aza-heterocyclyl or cycloalkyl options; X is defined by linkage forms involving C(O)N(R3)(C0-6 alkylene) or (C0-6 alkylene)-N(R3)C(O); and RA, including Y1, and R1 through R7 are restricted to the specified ring-size and functional-group sets.
Table-listed compound selection
A compound in any one of Tables 1, 2, or 3-A, or a pharmaceutically acceptable salt thereof, as explicitly listed in the tables.
LpxC inhibition by effective exposure
A method of inhibiting the activity of LpxC by exposing LpxC to an effective amount of a compound of claim 1 to inhibit the activity of LpxC.
Therapeutic bacterial infection treatment
A method of treating a bacterial infection in a patient by administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
Overall, the claims are directed to a constrained Formula I structural framework with defined ring, linkage, and substituent options, together with explicit table selection and therapeutic-use methods directed to LpxC inhibition and treatment of bacterial infection.
Stated Advantages
Inhibiting the activity of LpxC.
Inducing death of bacterial cells.
Treating a bacterial infection in a patient.
Providing antibacterial coverage across gram-negative, gram-positive, aerobic, and anaerobic bacteria.
Formulation and pharmaceutical composition use, including medicament kit coverage.
Antibacterial and therapeutic benefit by treating bacterial infection in a patient via administering a therapeutically effective amount of a compound of claim 1.
Documented Applications
Methods of inhibiting the activity of LpxC by exposing LpxC to an effective amount of a compound represented by Formula I or a pharmaceutically acceptable salt thereof.
Methods of treating a bacterial infection in a patient by administering a therapeutically effective amount of a compound represented by Formula I or a pharmaceutically acceptable salt thereof.
Antibacterial effect described as inducing death of bacterial cells.
Combination therapy.
A medicament kit.
Pharmaceutical compositions with dosing/formulation routes.
Biochemical evaluation of LpxC inhibition using an in vitro substrate deacetylation assay with IC50 values.
MIC testing versus Escherichia coli and Pseudomonas aeruginosa, including wild-type and efflux-knockout strains.
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