5-membered heteroaryl carboxamide compounds for treatment of HBV
Inventors
Haydar, Simon Nicolas • Li, Leping • Bures, Mark G. • Rai, Roopa • Bannen, Lynne • Walker, Michael
Assignees
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Publication Number
US-11560370-B1
Publication Date
2023-01-24
Expiration Date
Abstract
The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds, and pharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating Hepatitis B (HBV) infection.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, including 5-membered heteroaryl carboxamide compounds and substituted pyrazole/carboxamide scaffolds defined by extensive structural variables. The core scaffold is characterized by heteroatom selections for X1 through X6, linker L being a bond or C1-6 alkylene, and linker L1 options including bond, C1-6 alkylene, O, NRc, C(O), C(O)NRc, S(O)t, and S(O)tNRc. Additional structural definition is provided through variables such as Rx1, Ra/Rb/Rc, Rd, R0/R6/R8/R11, R1, R2, and R3.
R1 is selected from phenyl, naphthyl, C3-6 monocycloalkyl, C3-6 monoheterocycloalkyl, or 5-6 membered monocyclic heteroaryl, optionally substituted with one to three independently selected R11 groups. R2 is defined as RaRbN—, and R3 is selected from R5, R6, or R5-L1—, including a fused-ring relationship in which R4 and R8 together with the carbon atom to which they are attached form a group. The disclosure also states structural variation through R4a, R4b, R5, R5a, R5b, R6a, R7, and R7a, with indexed constraints including q, r, t, w, and v.
The document further describes a class of synthesized candidate compounds built on a 5-amino-1-methyl-1H-pyrazole-4-carboxamide core together with a 3-chloro-4-fluorophenyl group and an octahydropentalen core. The described examples include variants with imidazolidinone/oxazolidinone type substituents, hydroxyimino-derived amino reductions, sulfonamide substitutions, and sulfur-containing substituent variants. The disclosure also includes diastereomeric pairs, chiral HPLC or SFC separation, characterization data such as 1H NMR and LCMS/MS calcd/found values, and HBV-related subject matter including HBV core protein assembly disruption, pharmaceutical compositions, kits, and treatment of hepatitis B infection.
Claims Coverage
The consolidated claims cover a Formula I compound defined by extensive structural variable assignment and a general compound or pharmaceutically acceptable alternative. Across the claims, the inventive features include the heteroatom pattern, linker classes, aryl and heteroaryl substitution rules, and linked substituent relationships; dependent claim text also ties these compounds to pharmaceutical compositions and HBV treatment.
A compound of formula i with defined heteroatom pattern
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein X1 is NRx1, X2 is N, X3 is selected from O, NR7, CR4R8, C(O), S(O)t, C≡CR4R0—, or C≡NR4, and X4 and X6 are independently O or S, with X5 being O, S, or NR0.
Defined linker units L and L1
L is a bond or C1-6 alkylene, and L1 is a bond, C1-6 alkylene, O, NRc, C(O), C(O)NRc, S(O)t—, or S(O)tNRc.
Broad substituent set for core functional groups
Rx1, Ra, Rb, and Rc are independently selected from hydrogen, C1-6 alkyl, haloC1-6 alkyl, and C3-6 monocycloalkyl; Rd is hydrogen, OH, C1-6 alkyl, or C1-6 alkoxy; and R0, R6, R8, and R11 are independently selected from hydrogen, halogen, OH, CN, NO2, oxo, hydrazino, formyl, azido, silyl, siloxy, HOC(O)—, RaRbN—, RaRbNS(O)t—, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 monocycloalkyl, and other listed alkyl, alkoxy, halo, and sulfonyl-type options.
Aryl and heteroaryl substitution rules
R1 is selected from phenyl, naphthyl, C3-6 monocycloalkyl, C3-6 monoheterocycloalkyl, or 5-6 membered monocyclic heteroaryl, optionally substituted with one, two, or three independently selected R11 groups.
R2 and R3 linkage and fused-ring formation
R2 is RaRbN—; and R3 is selected from R5, R6, or R5-L1—, or R4 and R8 together with the carbon atom to which they are attached form a group, with further definitions for R4a, R4b, R5a, R5b, R6a, R7, and R7a.
Quantified substitution ranges
q, r, t, and w are independently selected for each occurrence from 0, 1, and 2, and v is independently selected for each occurrence from 0, 1, 2, and 3.
Pharmaceutical composition and HBV treatment
A pharmaceutical composition containing the compound or its pharmaceutically acceptable salt with a pharmaceutically acceptable excipient, and a method for treating Hepatitis B (HBV) infection by administering a therapeutically effective amount to a subject in need.
The claims are centered on a Formula I scaffold with explicitly defined heteroatom placements, linker options, and substituent-selection rules, together with a general compound claim in the family. Dependent claim coverage also extends to pharmaceutical compositions and treatment of Hepatitis B (HBV) infection by administration.
Stated Advantages
No explicit advantages are described in the provided patent text.
Documented Applications
Treating hepatitis B (HBV) infection by administering a therapeutically effective amount of a Formula I compound or pharmaceutically acceptable salt to a subject in need.
Treating hepatitis B (HBV) infection using a pharmaceutical composition containing the compound or its salt together with a pharmaceutically acceptable excipient.
Providing pharmaceutical compositions and kits for HBV treatment, including compositions using pharmaceutically acceptable excipients/carriers and enteric material.
Biological testing in HepAD38 cells for HBV viral load (qPCR) and associated EC50 activity (with CC50 referenced via Table 17).
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