Hepatitis B core protein modulators
Inventors
Turner, William • Maag, Hans • Francis, Samson
Assignees
Indiana University Research and Technology Corp • Assembly Biosciences Inc
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Publication Number
US-10766890-B2
Publication Date
2020-09-08
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 invention relates to hepatitis B virus core protein allosteric effector/core protein allosteric modifier compounds. The disclosure defines a compound represented by a scaffold structure with Y being S(O) with y equal to 2, Rz being H, and pharmaceutically acceptable salts of the compound, together with extensive Markush-style variability for R21, R22, R63, R69, q, and R4 through R10.
The compounds are characterized by options for X2 selected from S(O)w, O, CH2, or NR', and by ring and heteroaryl selections around an amide-linked aromatic scaffold. The scaffold includes a sulfone/sulfonamide-like motif and peripheral aromatic substituents, with dependent definitions constraining particular substituent sets including R21, R22, R63, and q.
The disclosure states that the compounds modulate hepatitis B virus core protein behavior, including effects on Cp multimerization and capsid assembly. The patent also presents substituted analogs and analytical characterization for multiple compounds while maintaining the retained core scaffold and varying peripheral aromatic substituents.
Claims Coverage
The provided claim set includes one broad independent compound claim directed to a variable scaffold with fixed core constraints and extensive substitution sets, plus a hepatitis B treatment use claim. In total, the identified inventive features center on the constrained scaffold, substitution options, and the hepatitis B use claim.
CpAM/CpAM-like compound scaffold with defined core constraints
A compound represented by a scaffold structure with Y as S(O) where y is 2, Rz as H, and pharmaceutically acceptable salts thereof, together with extensive Markush-style options for substituents including R21, R22, R63, R69, q, and R4 through R10.
Optional X2 selection within the core linkage
The compound is defined with X2 selected from S(O)w, O, CH2, or NR', with associated selection sets defining permitted options for R69 and additional functional-group-containing substituents.
Substituent narrowing via R21 selection
A compound from the defined scaffold in which R21 is selected from H and C1-6 alkyl.
Substituent narrowing via R22 selection
A compound from the defined scaffold in which R22 is selected from a specified set of substituents, including hydroxyl, nitro, cyano, carboxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NR'R'', and multiple aryl, heteroaryl, cycloalkyl, sulfonyl, and sulfinyl-form options.
R63 functional-group set with optional additional substitution and heteroaryl/aryl options
A compound in which R63 is independently selected from a defined group that includes H, halogen, hydroxyl, nitro, cyano, carboxy, C1-6 alkyl, substituted or unsubstituted aryl, heteroaryl, benzyl, C1-6 alkoxy, C(O)C1-6 alkyl, C(O)C1-6 alkoxy, and S(O)w- and NR'-S(O)w-substituted variants.
Additional structural element involving X2-C1-6alkylene-R69
A compound from the scaffold wherein R63 is selected as defined and includes the additional structural element X2C1-6alkylene-R69 with R69 selected from H, halogen, hydroxyl, nitro, cyano, C1-6 alkyl, C(O)O-C1-6 alkyl, heterocycle, heteroaryl, phenyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, carboxy, NR'R'', C(O)-C1-6 alkyl, C(O)-C1-6 alkoxy, C3-6 cycloalkyl, and multiple S(O)w- and NR'-S(O)w-substituted variants.
Numeric parameter restriction q equals 0
A compound from the defined scaffold in which q is equal to 0.
Hepatitis B treatment by administering the compound
A method for treating hepatitis B infection in a patient by administering an effective amount of the compound defined in the independent claim.
Overall, the claims coverage centers on a defined sulfone/sulfonamide-like scaffold with fixed core constraints, broad substitution variability, and dependent narrowing of specific substituent choices and the numeric parameter q = 0. The claim set also includes a hepatitis B treatment method based on administering an effective amount of the claimed compound.
Stated Advantages
The compounds modulate hepatitis B virus core protein behavior, including effects on Cp multimerization and capsid assembly.
The disclosure indicates potential impact on cccDNA transcription, RNA stability, and protein-protein interactions.
The disclosure positions the compounds for therapeutic application in treating hepatitis B infection.
Documented Applications
Treating hepatitis B infection in a patient by administering an effective amount of the compound.
Use in combination with other anti-HBV agents, including capsid assembly promoters, nucleos(t)ide analogs, and interferon.
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