Cyclic sulfamide compounds and methods of using same
Inventors
Turner, Jr., William W. • Li, Leping • Haydar, Simon Nicolas • Bures, Mark G. • Rai, Roopa • Francis, Samson • Arnold, Lee D.
Assignees
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Publication Number
US-11078170-B2
Publication Date
2021-08-03
Expiration Date
Abstract
The present disclosure provides, in part, cyclic sulfamide compounds, and pharmaceutical compositions thereof, useful as modulators of Hepatitis B (HBV) core protein, and methods of treating Hepatitis B (HBV) infection.
Core Innovation
The disclosure provides compounds of Formula I, or pharmaceutically acceptable salts thereof, with w being 2 and with defined substituent variables R1, R2, R3, R4, R5, R6, R33, and related parameters including q, t, r, and r2. R1 is phenyl or pyridyl, R2 is hydrogen, and the compound includes broad optional substitution patterns on aryl and heteroaryl groups, together with provisos that restrict allowed combinations for specific R3 cases such as thiophen-2-yl, furan-2-yl, pyrazol-4-yl, and phenyl.
The structural definitions further specify R4 as hydrogen or C1-6 alkyl optionally substituted with one, two, or three substituents from a defined group, R5 as hydrogen or C1-6 alkyl optionally substituted with selected substituents, and R6 as hydrogen or C1-6 alkyl. R33 is independently selected for each occurrence from a broad substituent set including halo, —OH, —CN, —NO2, oxo, hydrazino, formyl, azido, silyl, siloxy, and sulfur- or carbonyl-containing groups, and phenyl or 5–6 membered monocyclic heteroaryl ring systems optionally substituted with one, two, or three substituents from the same defined set.
The disclosure also includes HBV-targeting thiadiazine and thiadiazinane carboxamide 1,1-dioxide compounds, including named HBV-CSU series members, stereoisomers designated ISO-I and ISO-II, and related intermediates. The described examples are supported by analytical characterization such as LCMS, mass spectrometry, and 1H NMR, and the provided content repeatedly ties the compound families to Formula I scaffold definitions and substitution patterns.
Claims Coverage
The consolidated claim coverage centers on one independent claim, which defines a compound of Formula I, or a pharmaceutically acceptable salt thereof, with w fixed at 2 and with broadly defined substituent variables and parameter constraints. The inventive features are the Formula I scaffold, the substituted aryl and heteroaryl selections, and the numeric/proviso restrictions that narrow specific R3 and R33 combinations.
Formula I compound with w fixed at 2
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein w is 2 and R2 is hydrogen.
Phenyl or pyridyl R1 with optional substitution
R1 is phenyl or pyridyl optionally substituted with one, two, or three substituents independently selected from a defined group including halo, —OH, —CN, —NO2, oxo, hydrazino, formyl, azido, silyl, siloxy, and sulfur-containing or carbonyl-containing groups.
Defined R3 framework with R4, R5, and R6 options
R3 is selected from a defined group of structures, with R4 being hydrogen or C1-6 alkyl optionally substituted with one, two, or three substituents from the defined set, R5 being hydrogen or C1-6 alkyl optionally substituted with selected substituents, and R6 being hydrogen or C1-6 alkyl.
R33-defined heteroaryl and aryl substitution
R33 is independently selected for each occurrence from a broad substituent group, including phenyl and 5–6 membered monocyclic heteroaryl rings having one, two, or three heteroatoms selected from O, N, and S, each optionally substituted with one, two, or three substituents from the defined set.
Parameter constraints and provisos for specific R3 selections
Each occurrence has q equal to 0, 1, or 2; t equal to 1 or 2; r equal to 0, 1, or 2; and r2 equal to 0, 1, 2, or 3, with provisos that restrict thiophen-2-yl, furan-2-yl, pyrazol-4-yl, and phenyl cases.
The claim coverage is a broad Formula I scaffold with explicit substituent definitions for R1 through R6 and R33, together with numeric ranges and provisos that restrict particular heteroaryl and phenyl embodiments.
Stated Advantages
Only one stereoisomer shows significant activity for HBV viral production activity.
Documented Applications
Pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Method for treating Hepatitis B (HBV) infection by administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need.
HBV viral production activity assay in HepAD38 cells.
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