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-10934295-B2
Publication Date
2021-03-02
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 a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
Core Innovation
The invention relates to compounds of Formula (I), including tautomers and pharmaceutically acceptable salts of the compound or tautomer. The compounds are defined by variable substituents R1 through R9 and structural parameters W, X, and Y, with restricted selections for halo, alkyl, haloalkyl, alkenyl, heterocycloalkyl, and heteroaryl groups. The scaffold includes an amide-like carbonyl and a halogenated phenyl group, and the document describes structure depictions consistent with the Formula (I) framework, including substituted ring motifs and stereochemical indications.
In Formula (I), R1 and R2 are each selected from halo, while R3 is selected from C1-6 alkyl, NRc1Rd1, NO2, ORa1, SRa1, S(O)2Rb1, and 5- to 6-membered heterocycloalkyl, with optional substituent patterns defined for the alkyl and alkoxy components. R4 is selected from H, C1-6 alkyl, and C2-6 alkenyl, with optional substitutions including ORa2, SRa2, NRc2Rd2, and NRc2C(=NRc2)NRc2Rd2. Additional variability is provided by selections for R5, R7, R8, R9, and Re2 within the enumerated sets.
A central part of the structural definition is the relationship among W, X, and Y, and the combined ring-forming constraints. X is selected from O, NR, S, and CH2, and Y is N or CR3. W is selected from CR6A R6B and NR6A, and either R6A and R6B define an oxo group, or R6A and R4, together with the carbon atom bearing R4, the W atom bearing R6A, and the X atom connecting W to that carbon, form a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms.
Claims Coverage
The consolidated claim coverage centers on a single independent claim defining a Formula (I) compound, tautomer, or pharmaceutically acceptable salt with multiple constrained substituent groups and structural link parameters W, X, and Y. Dependent claims further narrow the scope by fixing specific variable choices and by imposing ring-forming relationships that produce a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms.
Formula (I) compound framework with tautomer and salt coverage
A compound of Formula (I), or a tautomer or a pharmaceutically acceptable salt of the compound or tautomer.
Halogen substitution on R1 and R2
R1 and R2 are each selected from halo.
Restricted R3 selection
R3 is selected from C1-6 alkyl, NRc1Rd1, NO2, ORa1, SRa1, S(O)2Rb1, and 5- to 6-membered heterocycloalkyl, with optional substitution patterns defined for the alkyl and alkoxy components.
Defined R4 side-chain options
R4 is selected from H, C1-6 alkyl, and C2-6 alkenyl, with optional substitutions including ORa2, SRa2, NRc2Rd2, and NRc2C(=NRc2)NRc2Rd2.
Link parameter X and ring construction via W
X is selected from O, NR, S, and CH2; W is selected from CR6A R6B and NR6A; Y is N or CR3; and R6A and R6B are limited to defined options including formation of an oxo group or a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms with R4 and X.
Residue selections for R5, R7, R8, R9, and Re2
R5 is selected from H and C1-4 alkyl; R7 is selected from C1-4 alkyl, C1-4 haloalkyl, and C3-5 cycloalkyl; R8 is selected from H, C1-4 alkenyl, C1-4 haloalkyl, and C1-4 alkyl optionally substituted with amino, C1-4 alkoxy, C3-5 cycloalkyl, and 3- to 6-membered heterocycloalkyl; R9 is selected from H and halo; and Re2 is selected from H and C1-4 alkyl.
Overall, the claim coverage is anchored in a Formula (I) chemical scaffold with constrained halogen substitution, defined sets for multiple substituents, and explicit ring-connection rules involving W, X, Y, R6A, R6B, and R4. The dependent features further refine these definitions by specifying variable selections and ring-topology outcomes.
Stated Advantages
Antimicrobial compounds designed by structure-based drug design targeting bacterial ribosome function.
Documented Applications
Treating, preventing, reducing risk, and/or delaying onset of microbial infections using the described compounds.
Administration routes include oral, parenteral, intravenous, otic, ophthalmic, nasal, and topical.
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