Penicillin-binding protein inhibitors
Inventors
Burns, Christopher J. • DAIGLE, Denis • Chu, Guo-Hua • HAMRICK, Jodie • Boyd, Steven A. • Zulli, Allison L • Mesaros, Eugen F. • Condon, Stephen M. • TROUT, Robert E. Lee • MYERS, Cullen L. • Xu, Zhenrong
Assignees
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Publication Number
US-12173018-B2
Publication Date
2024-12-24
Expiration Date
Abstract
Described herein are certain boron-containing compounds, compositions, preparations and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds described herein inhibit penicillin-binding proteins. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
Core Innovation
The invention relates to compounds and pharmaceutically acceptable salts, solvates, stereoisomers, tautomers, or N-oxides thereof, having one of the defined formulas with Ring A as a 6-membered heteroaryl. The structures are controlled by multiple substituent variables including Y, R32, R33, R34, W1, W2, R90, R91, p, u1, u2, Z, Ra, Rb, Rc, and Rd, with permitted groups including halogen, optionally substituted alkyl, hydroxyl, alkoxy, amino-containing groups, sulfonamide groups, and carboxylic acid, ester, or amide carbonyl-containing groups.
The disclosure further describes benzo[e][1,2]oxaborinine carboxylic acid derivatives and related boron-containing scaffold compounds, including stereodefined chiral examples and diastereomeric variants. The compounds include substituted aromatic, heteroaryl, and side-chain variations, together with boron-containing moieties and carboxylic acid functionality. Analytical characterization is reported for the examples, including ESI-MS-type reporting and stereochemical assignments.
The document also describes specific compound families as penicillin-binding protein inhibitors and presents formula-defined members with heteroaryl substitution patterns and related structural drawings, including variants with halogen, hydroxyl, alkoxy, amide, sulfonyl, and carboxylic acid or ester-type substituents. The compounds are provided in compound form and as pharmaceutically acceptable variants, and pharmaceutical compositions are described.
Claims Coverage
The claim set centers on a single independent compound claim defining a broad structural formula with Ring A as a 6-membered heteroaryl. The coverage includes seven inventive features: the defined scaffold, the Y substituent set, the W1/W2 and related variable framework, the Z/R60/R61 definition, parameter constraints on p/u1/u2, additional substituent limits, and therapeutic administration for bacterial infection.
Formula-defined heteroaryl Ring A scaffold
A compound or pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or N-oxide having one of the formulas in which Ring A is a 6-membered heteroaryl.
Controlled Y substituent set
Each Y is independently halogen, optionally substituted alkyl, —OH, —OR34, —OC(=O)R34, —NR32R33, —NR32C(=O)R34, —NR32C(=O)OR34, —NR32S(=O)0,1,2R33, —NR32S(=O)0,1,2R34, —C(=O)OH, —C(=O)OR34, or —C(=O)NR32R33, with R32 and R33 independently hydrogen or optionally substituted alkyl and R34 optionally substituted alkyl.
Defined W1/W2 and Z substituent framework
Each W1 and W2 is independently —C(=O)— or —C(R91)2—, with R90 hydrogen or optionally substituted alkyl, each R91 independently hydrogen or optionally substituted alkyl, and Z hydrogen, R61, —R60OC(=O)R61, or —R60OC(=O)OR61, where each R60 is independently —CH2— or —CH(CH3)— and each R61 is independently optionally substituted alkyl.
Parameter constraints on p, u1, and u2
p is 1-3, and u1 and u2 are each 1 or 2.
Additional substituent limits
Ra, Rb, and Rc are independently hydrogen, halogen, cyano, alkyl, or —OH, and Rd is hydrogen or alkyl.
Dependent narrowing of the scaffold
Dependent refinements restrict values such as p equal to 2 or 3, Ring A selected from pyridine, pyrimidine, pyrazine, or pyridazine, and selected substituent positions such as hydrogen or fluoro.
Therapeutic administration for bacterial infection
A method for treating a bacterial infection in a subject by administering an effective amount of the compound or a pharmaceutically acceptable form thereof.
The claim coverage is directed to a structurally defined compound class with a 6-membered heteroaryl Ring A and a broad but explicit substitution-variable framework. Dependent claims further narrow the scaffold by discrete parameter choices and selected Ring A or substituent options, and at least one claim adds therapeutic use for treating bacterial infection.
Stated Advantages
Inhibits bacterial penicillin-binding proteins (PBPs) by modulating transpeptidase function.
Aims to treat bacterial infections, including antibiotic-resistant strains.
Documented Applications
Treating a bacterial infection in a subject by administering an effective amount of the compound or its pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or N-oxide form.
Pharmaceutical compositions containing the described compounds with pharmaceutically acceptable excipients.
Penicillin-binding protein inhibitor use is described for the compounds.
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