Substituted pyrrolo[2,3-d]pyrimidines as antimicrobials
Inventors
Duffy, Erin M. • Bhattacharjee, Ashoke • Kanyo, Zoltan F. • Ippolito, Joseph A. • Marra, Andrea
Assignees
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Publication Number
US-12297201-B2
Publication Date
2025-05-13
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 (A):or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
Core Innovation
The patent provides compounds defined by Formula (A) and includes pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. The core structure is expressed through multiple substituent variables, including J, R1, R2, R3, R4, R5, R6, R7, R8, and X, with J defined by a specific structural choice in Formula (A). The substituent framework allows R1, R2, and R3 to vary among H or C1-3 alkyl, subject to defined combinations.
A key structural element is that R5 and R7, together with the carbon and nitrogen atoms to which they are attached, form a heterocyclyl having specified formulas, with additional optional substitution on a ring carbon atom by a C1-6 alkyl substituent. In related embodiments, R6 is defined as H or one of C1-6 alkyl, C2-6 alkenyl, or C3-6 cycloalkyl, and the C1-6 alkyl substituent is optionally substituted with selected groups independently chosen from halogen, C(O)ORa, ORa, SRa, SC(NH)NH2, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl.
The invention further defines X as a 5- or 6-membered heterocyclyl or phenyl, optionally substituted with one or more independently selected Rx substituents, where each Rx may be halogen, C1-6 alkyl, C1-4 haloalkyl, C(O)Rc, C(O)ORc, NRcRc, ORc, C3-6 cycloalkyl, or aryl. Additional structural diversity is obtained where two adjacent Rx substituents form a 5- or 6-membered ring, and where each Rb and Rc and Rd have explicit allowed identities and substitution constraints.
Claims Coverage
The provided independent claim coverage includes one independent claim (clm-00001) covering compounds of Formula (A) with defined substituent-variable constraints and optional pharmaceutically acceptable salts, stereoisomers, and tautomers. The claim includes alternative compositions of R1/R2/R3 and defines heterocyclic formation via R5/R6/R7 and the atom-attached ring closures, along with a defined Rx/Rb/Rc/Rd substitution system for X.
Formula (A) compound definition
A compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein J is defined and wherein R1, R2, and R3 are selected according to the specified options (H or C1-3 alkyl combinations).
R5/R6/R7 heterocyclyl ring formation and allowed heterocycle substitutions
R5 is H or C1-6 alkyl, and R6 and R7 together with the carbon and nitrogen atoms to which they are attached form a heterocyclyl having any of the specified formulas, optionally substituted on a ring carbon atom with a C1-6 alkyl substituent; or wherein R5 and R7 form a heterocyclyl having any of the specified formulas and R6 is H, C1-6 alkyl, C2-6 alkenyl, or C3-6 cycloalkyl with the C1-6 alkyl optionally substituted with groups independently selected from halogen, C(O)ORa, ORa, SRa, SC(NH)NH2, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl.
X group with independently selected Rx substituents and optional ring formation
X is a 5- or 6-membered heterocyclyl or phenyl, wherein the heterocyclyl or phenyl is optionally substituted with one or more independently selected Rx substituents, where each Rx is independently halogen, C1-6 alkyl, C1-4 haloalkyl, C(O)Rc, C(O)ORc, NRcRc, ORc, C3-6 cycloalkyl, or aryl, and wherein two adjacent Rx together with the atoms to which they are attached form a 5- or 6-membered ring.
Defined substitution rules for Rb, Rc, and Rd
Each Rb is independently C2-6 alkenyl, C(O)ORc, NRcRc, ORc, OC(NH)NH2, C3-6 cycloalkyl, or aryl; each Rc is independently H, C1-6 alkyl, CH2-aryl, C(O)aryl, or aryl wherein each C1-6 alkyl and each aryl is optionally and independently substituted with one or more Rd substituents; and each Rd is independently C1-3 alkyl, NH2, NHC1-3 alkyl, N(C1-3 alkyl)2, NO2, OH, or OC1-3 alkyl.
Across the provided independent claim, the coverage centers on compounds of Formula (A) with defined R1/R2/R3 alternatives, a heterocyclyl constructed from R5/R6/R7 with specific allowed substitution patterns, and an X group that supports defined Rx substitution, including optional ring formation, together with explicit constraints on Rb, Rc, and Rd identities and their optional substitutions.
Stated Advantages
Activity against bacterial pathogens, including drug-resistant pathogens, as supported by MIC/MIC90 threshold statements.
The compounds are designed to bind the bacterial ribosome and thereby inhibit or modulate bacterial ribosome function.
Therapeutic uses include treating, preventing, reducing risk of, or delaying onset of microbial infections in humans and animals.
Documented Applications
Treatment and/or prevention of microbial infections using ribosome-binding compounds active against bacterial pathogens including ESKAPE-related and drug-resistant strains.
In vitro antibacterial activity reporting against bacteria including Enterococcus faecium, MRSA, Enterobacteriaceae (ESBL, AmpC), carbapenemase-associated classes (A, B, D), Pseudomonas aeruginosa, and Acinetobacter baumannii, including MIC/MIC90 threshold statements.
Methods of treating, preventing, reducing risk of, or delaying onset of microbial infection in humans and animals using the described compounds and pharmaceutical compositions.
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