Antimicrobials and methods of making and using same
Inventors
Duffy, Erin M. • Bhattacharjee, Ashoke • Kanyo, Zoltan F. • Ippolito, Joseph A.
Assignees
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Publication Number
US-11098047-B2
Publication Date
2021-08-24
Expiration Date
Abstract
The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. In some embodiments, the present disclosure provides a compound of Formula (I) or tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
Core Innovation
The disclosure describes compounds of Formula (I), including tautomers and pharmaceutically acceptable salts, defined by multiple variable substituents and ring-forming relationships. The compounds share a polycyclic or heterocyclic core with nitrogen atoms and carbonyl functionality, and the structures include halogenated aryl motifs, including fluorine and chlorine, together with variable side chains and stereochemical diversity.
A key structural feature is the defined ring formation among R6 and R7A with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms, forming a 5- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S. X is selected from O and NR8, W is selected from N and CR4, and additional variables such as R8A, L, R11, R12, R13, R14, and RB are each constrained by enumerated group sets and optional ring-formation relationships.
The disclosure further presents specific instantiated compounds within the broad Formula (I) chemical space, including variants with halogen substitution patterns, sulfur-containing substituents, heteroaryl or heterocycloalkyl substituents, and terminal functional group changes such as hydroxy, amino, and alkoxy-like groups. The examples also show stereochemical variation and preserve the same general fused nitrogen-containing heterocyclic scaffold across the described embodiments.
Claims Coverage
The consolidated claim coverage centers on one independent claim, clm-00001, directed to a compound of Formula (I), including tautomers and pharmaceutically acceptable salts. The claim defines a broad scaffold by enumerating permitted substituent sets at multiple positions and by imposing specific ring-forming constraints; it covers three main inventive features in addition to the detailed substituent selections.
Formula (I) compound with tautomer or pharmaceutically acceptable salt
A compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.
Heterocycloalkyl ring formation via R6, R7A, and X
R6 and R7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a 5- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S.
Defined substituent sets across the Formula (I) scaffold
R1, R2, R3, W, R4, R5, R8, R8A, R9, R10, L, R11, R12, R13, R14, RB, and related variables are each selected from the stated groupings, including halogen, alkyl, alkoxy, haloalkyl, heteroaryl, heterocycloalkyl, and ring-forming options, with additional optional oxo substitution in specified ring systems.
The claim coverage is defined by a Formula (I) scaffold with broad but explicit substituent selections and key ring-formation constraints, especially the heterocycloalkyl formation involving R6, R7A, and X. The scope also includes additional ring-forming options involving R11 and RB, together with the defined substituent sets across the remaining variables.
Stated Advantages
Treating, preventing, reducing risk, and/or delaying onset of microbial infections in humans or animals.
Provides compounds useful for treating or preventing microbial infection or reducing risk or delaying onset of infection.
Intended to be useful against susceptible and moderate-to-severe infections.
Stated coverage includes activity relevant to ESKAPE pathogens and multi-drug resistant microorganisms.
Includes compounds with biological activity against multiresistant Gram-negative bacteria.
Documented Applications
Antibacterial treatment and prevention of microbial infection using Formula (I) compounds and pharmaceutical compositions.
Pharmaceutical compositions and medicaments for treating or preventing microbial infection, reducing risk, or delaying onset in a subject.
Use against susceptible and resistant microorganisms, including gram-positive, gram-negative, and anaerobic microorganisms.
Infection indications explicitly listed include skin infections, pneumonia, complicated intra-abdominal infection, complicated urinary tract infection, acute pelvic infection, bacteremia/septicemia, meningitis, and surgical prophylaxis.
Use against ESKAPE pathogens, multi-drug resistant microorganisms, and biological-weapon microorganisms.
Activity against bacterial ribosomes and inhibition of translation or protein synthesis, including surface plasmon resonance (SPR), fluorescence polarization, protein synthesis inhibition, and translation-only assays.
MIC microdilution screening against listed bacteria, including ESKAPE pathogens and other drug-resistant strains.
Gram-negative antibacterial activity characterization and antimicrobial testing of pyrrolocytosine protein synthesis inhibitors.
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