Aromatic amides and uses thereof
Inventors
Haydon, David John • Czaplewski, Lloyd George • Stokes, Neil Robert • Davies, David • Collins, Ian • Palmer, James T. • Mitchell, Jeffrey Peter • Pitt, Gary Robert William • Offermann, Daniel
Assignees
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Publication Number
US-9511073-B2
Publication Date
2016-12-06
Expiration Date
Abstract
The present invention provides compounds of Formula (I): and salts, racemates, isomers, diastereoisomers, enantiomers, hydrates, solvates, N-oxides, pharmaceutically acceptable derivatives or prodrugs thereof. Also provided the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture.
Core Innovation
The patent provides compounds of Formula (I), Formula (Ia), and general Formula (II), and related forms including salts, racemates, diastereoisomers, enantiomers, hydrates, solvates, N-oxides, and prodrugs. The compounds are defined by substituted C6-10-membered monocyclic or fused bicyclic aryl groups or specified heteroaryl options for W, heteroatom selections X, Y, and Z, and constrained substituent patterns for R1, R2, R3, t, and x, with optional fused ring formation through A and B.
The disclosure identifies a selected group of specific named compounds and representative stereochemical forms, together with compositions comprising such compounds. Across the formula sets, the substituent definitions specify optional substitution rules for alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl groups, including substituent classes for R4, R5, R6, and related carbonyl, phosphoryl, sulfinyl, and sulfonyl options.
The patent also describes preparation of Formula (I) compounds by coupling a compound of Formula (III) with a leaving-group-containing fragment LG-C(R3)(R39)-W. The disclosure further describes substituted oxazole/thiazole cores and fused heteroaryl-containing benzamide targets, including representative intermediates and final substituted benzamide and bromo derivatives, with protection-group strategies and stereochemically defined intermediates.
Claims Coverage
The claim set covers structurally defined compound families, compositions, treatment methods, and a coupling-based preparation process. The independent inventive features comprise the compound structures of Formula (I), Formula (Ia), and general Formula (II), the selected compound groups and derivative forms, methods of treating bacterial infection by administering the compounds, and preparation of Formula (I) compounds by coupling Formula (III) with a leaving-group-containing fragment.
Compound of formula (I)
A compound of Formula (I) or a salt, racemate, diastereoisomer, enantiomer, hydrate, solvate, N-oxide, or prodrug thereof, wherein W is a substituted C6-10-membered monocyclic or fused bicyclic aryl group or an optionally substituted 5-6-membered monocyclic heteroaryl or a 9-membered fused bicyclic heteroaryl group; R1 and R2 are each independently halo or H; R3 is selected from Ct alkyl-R4, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6 aryl, and 5-6 membered heterocyclyl; t is 0, 1, 2 or 3; R39 is H; and x is 0 or an integer from 1 to 2.
Compound of formula (Ia)
A compound of Formula (Ia) or a salt, racemate, diastereoisomer, enantiomer, hydrate, solvate, N-oxide, or prodrug thereof, wherein X and Y are each independently O, N, S, or a carbon atom having an optional substituent; Z is O, N, S, or C4B; A and B are selected to define substituent patterns and may join to form an optionally substituted 6-membered fused ring system; and R1, R2, R3, t, R4, and x are as defined.
Compound of general formula (II)
A compound of general Formula (II) or a salt, diastereoisomer, hydrate, solvate, N-oxide, or prodrug thereof, wherein X and Y are each independently O, N, S, or a carbon atom having an optional substituent; Z is O, N, S, or C4B; A and B are selected to define substituent patterns and may join to form an optionally substituted 6-membered fused ring system; and R1, R2, R3, t, R4, and x are as defined.
Selected compound group and derivative forms
A compound selected from the group consisting of the listed specific compounds and related stereochemical forms, or a salt, racemate, diastereoisomer, enantiomer, hydrate, solvate, N-oxide, or prodrug thereof.
Method of treating a bacterial infection by administering formula (I) compounds
A method of treating a bacterial infection in a subject comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, racemate, diastereoisomer, enantiomer, hydrate, solvate, N-oxide or prodrug thereof.
Coupling-based process for preparing formula (I) compounds
A process for preparing a compound of Formula (I) or a salt, racemate, diastereoisomer, enantiomer, hydrate, solvate, N-oxide, or prodrug thereof comprising coupling a compound of Formula (III) with a compound of general formula LG-C(R3)(R39)-W, where LG is a leaving group.
Overall, the claims cover the defined compound families, selected compound groups, treatment of bacterial infection by administering the compounds, and preparation of Formula (I) compounds by coupling Formula (III) with a leaving-group-containing fragment of the required structural scope.
Stated Advantages
Improved resistance/MPC-related profiles for the bromo-substituted oxazole/thiazole subclass.
Activity against the FtsZ G196A mutation for the bromo-substituted oxazole/thiazole subclass.
Metabolic stability improvements associated with R3 substitution and enantiomeric R and S forms [as referenced in partial content].
Documented Applications
Treating a bacterial infection by administering an effective amount of a compound of Formula (I) (including pharmaceutically acceptable salt/mixture/forms as defined).
Disinfecting a substrate affected by a bacterial infestation by applying a compound of Formula (I) (or related salt/mixture/form as defined) to the substrate.
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