Hepatitis B core protein allosteric modulators
Inventors
Turner, Jr., William W. • Arnold, Lee Daniel • Maag, Hans • Zlotnick, Adam
Assignees
Indiana University Research and Technology Corp • Assembly Biosciences Inc
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Publication Number
US-10183936-B2
Publication Date
2019-01-22
Expiration Date
Abstract
The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound.
Core Innovation
The disclosure relates to compounds represented by a formula in which Y is S(O)2, together with extensive substitution-variable definitions for Rm′, Rm, Rc, R78, R79, R′, R″, and moieties R4 through R10. The compounds include pharmaceutically acceptable salts and allow substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, and heteroaryl groups, including sulfur-oxidation and NR′-S(O)w-containing substituents.
The structures include benzimidazolinone/amide-like and sulfonamide-containing compounds, as well as fluorinated thioether-containing amide compounds, fluorinated thioether-containing diaryl amide compounds, and related benzamide-like or thio-linked carboxamide/urea-like scaffolds. The disclosure describes amide motifs, thioether or sulfur-oxide linkages, fused heteroaromatic and substituted anilide/heteroaryl arrangements, and variable aryl or heteroaryl substituents, including nitrogen-containing ring systems and fluorine-substituted variants.
The examples are characterized by structural depictions, formulae, molecular ion mass, LC-MS, UPLC purity, and 1H NMR chemical shifts in DMSO-d6. The record also includes synthetic sequences and intermediates for substituted thiazepine, benzamide, and related scaffolds, and describes in vitro evaluation of viral production and cellular viability for Example 56.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim defining a sulfur-oxide scaffold with Y = S(O)2 and extensive substituent-variable definitions, and on a hepatitis B infection treatment claim using the claimed compound with enumerated HBV agents. Dependent claims refine specific substituent choices, including H/F and H/methyl/F restrictions and an all-hydrogen variant.
Sulfur-oxide compound scaffold with broad substituent definitions
A compound represented by a formula wherein Y is S(O)2 and y is 2, with Rm′ and Rm each independently selected from hydrogen, halogen, alkyl, alkenyl, NR′R″, and hydroxyl; Rc is H; R78 and R79 are selected from an enumerated set including halogen, hydroxyl, nitro, cyano, carboxy, alkyl, alkenyl, alkynyl, alkoxy, NR′R″, carbonyl-containing groups, phenyl, heteroaryl, cycloalkyl, and sulfur-oxidation-containing substituents; and the compound includes pharmaceutically acceptable salts.
Optional substitution on alkyl, alkoxy, phenyl, and heteroaryl groups
Alkyl, alkoxy, cycloalkyl, phenyl, and heteroaryl groups may be optionally substituted by one, two, three or more substituents selected from the expressly listed groups, including halogen, hydroxyl, nitro, cyano, carboxy, alkyl, alkenyl, alkynyl, alkoxy, NR′R″, and sulfur-oxide or NR′-S(O)w-containing substituents.
Narrowed substituent selections for specific variables
Dependent embodiments restrict particular variables, including R7 or R6 selected from H or F, R10 selected from H, methyl, or F, and another embodiment sets multiple moieties, including R4, R5, R6, R7, R8, R9, R10, and R, to H.
Combination treatment for hepatitis B infection
A method of treating hepatitis B infection by administering a first compound of the defined formula together with one or more additional HBV agents selected from an explicitly enumerated group including HBV capsid assembly promoters, viral polymerase interfering nucleosides, viral entry inhibitors, HBsAg secretion inhibitors, disruptors of nucleocapsid formation, cccDNA formation inhibitors, antiviral core protein mutant, HBc directed transbodies, RNAi targeting HBV RNA, immunostimulants, TLR-7/9 agonists, cyclophilin inhibitors, HBV vaccines, SMAC mimetics, epigenetic modulators, kinase inhibitors, and STING agonists.
Overall, the claims coverage is anchored by a sulfur-oxide compound formula with Y = S(O)2, broad and explicitly enumerated substitution-variable options across multiple groups, and pharmaceutically acceptable salts. Dependent claims further narrow specific substituents and add a hepatitis B infection combination-treatment provision with a specifically enumerated set of HBV-directed agents.
Stated Advantages
Not explicitly described in patent.
Documented Applications
In vitro evaluation of viral production and cellular viability using HBV qPCR and AD38 cell viability in Example 56.
Treatment of hepatitis B infection by administering the disclosed compound alone or in combination with one or more additional HBV agents selected from the enumerated group of HBV-directed agents.
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