Linked purine pterin HPPK inhibitors useful as antibacterial agents

摘要

The disclosure provides linked purine pterin compounds and analogs thereof that are novel HPPK inhibitors. The HPPK inhibitors described herein are compounds and the pharmaceutically acceptable salts thereof of general Formula I;
The variables, e.g. A1 to A3, R1 to R4, L1, L2, B1, and B2 are described herein. Compounds and salts of Formula I bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing an HPPK inhibitor of Formula I and methods of treating a bacterial infection in a patient by providing one or more HPPK inhibitors of Formula I to the patient are also provided. Processes and intermediates useful for preparing compounds of Formula I are also provided. Methods of using the disclosed compounds to guide the development of additional novel anti-bacterial agents are also provided.

主权项

1. A compound or pharmaceutically acceptable salt thereof of the formula: wherein:is a 5 or 6-membered heterocyclic ring;
X is nitrogen, —N(A5)-, —C(A6)-, or —C(A6A7)-; A1 is hydrogen, oxo, amino, or aminoC1-C2alkyl; A2 is absent, hydrogen, or C1-C2alkyl; A3 is absent, or one or two substituents independently chosen from hydrogen, halogen, C1-C2alkyl, and C1-C2alkoxy; A5 is hydrogen or C1-C4alkyl; A6 and A7 are independently hydrogen, C1-C4alkyl, or C1-C4alkoxy; R1 is methylene optionally substituted with hydroxyl, halogen, C1-C2alkyl, or oxo; R2 is chosen from —NH—, —SH—, —S(═O)—, —S(═O)2—, —P(═O)—, and —P(═O)2—; L1 is an alkylene linker having from 1 to 4 carbon atoms, optionally containing 1 heteroatom selected from oxygen, nitrogen, and sulfur, and optionally containing 1 to 2 carbon-carbon double bonds, wherein L1 is unsubstituted or substituted with 1 or more substituents independently chosen from hydroxyl, halogen, amino, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; R3 is absent or R3 is an amide, heteroalkylene, cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl; and R3 is unsubstituted or substituted with 1 or more substituents independently chosen from hydroxyl, halogen, amino, C1-C4alkyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy; L2 is absent or L2 is an alkylene linker having from 1 to 4 carbon atoms, optionally containing 1 heteroatom selected from oxygen, nitrogen, sulfur, and phosphorus and optionally containing 1 to 2 carbon-carbon double bonds, wherein L2 is unsubstituted or substituted with 1 or more substituents independently chosen from oxo, hydroxyl, halogen, amino, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy;is a 5- or 6-membered monosaccharide ring or is an alkylene or heteroalkylene linker having from 1 to 4 chain atoms; and
B1 and B2 are independently chosen from hydrogen, halogen, hydroxyl, amino, C1-C2alkyl, C1-C2alkoxy, mono- or di-C1-C2alkylamino, aminoC1-C2alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.