Bicyclic compounds
Inventors
Vendeville, Sandrine • Raboisson, Pierre Jean-Marie Bernard • McGowan, David • Debing, Yannick
Assignees
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Publication Number
US-11957683-B2
Publication Date
2024-04-16
Expiration Date
Abstract
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, having a defined scaffold with variable substituents including Z1, R1, R2 and R3, R4 and R5, R6 and R7, R8, and R9, together with related groups R10A, R10B, and R11. The scaffold is defined by selections for n as 0 or 1 and Z1 as —C(=O)— or —NH—C(=O)—, and by broad structural categories for aryl, heteroaryl, heterocyclyl, alkyl, alkenyl, alkynyl, and haloalkyl variants.
The described embodiments define substituted pyrido[3,4-d]pyrimidinone analogs, heteroaryl amine building blocks, and related heteroaryl/benzo[d]imidazole/imidazo[4,5-b]-type scaffolds, including halogenated benzoyl groups, aminopyrimidine/carboxamide structures, and hydrochloride salts. The disclosure also includes multiple specific compound examples and intermediate scaffolds.
The document reports HBV-DNA antiviral testing for compounds of Formula (I) in HepG2.117 cells with EC50/CC50 categorization and presents example compound activities against HBV. It also describes pharmaceutical composition and therapeutic use for HBV and/or HDV, together with replication inhibition uses in connection with hepatitis B and hepatitis D.
Claims Coverage
The consolidated claim coverage centers on a Formula (I) compound claim with extensive structural variability and related refinements. The inventive features focus on the scaffold defined by Z1, R1, R2–R7, R8, R9, and the linked R10A/R10B/R11 patterns, including explicit conditional restrictions and enumerated substituent classes.
Formula (I) compound scaffold with defined variable substituents
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, with n as 0 or 1 and Z1 selected as —C(=O)— or —NH—C(=O)—, and with R1, R2 and R3, R4 and R5, R6 and R7, R8, R9, R10A, R10B, and R11 defined by specific chemical categories and constraints.
Diverse R1 substituent selection
R1 is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or the corresponding optionally substituted aryl(C1-4 alkyl), heteroaryl(C1-4 alkyl), or heterocyclyl(C1-4 alkyl) groups.
Substituent pattern for R2–R7
R2 and R3 are independently selected from hydrogen and the listed C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, monocyclic C3-6 cycloalkyl, aryl, heteroaryl, and heterocyclyl classes, including alkyl-substituted variants; R4 and R5 follow analogous classes; and R6 and R7 are independently hydrogen, an unsubstituted C1-4 alkyl, or an unsubstituted C1-4 haloalkyl.
R8 amine-linked or alkynyl substituent with constrained R10A/R10B
R8 is —NR10A R10B or an optionally substituted C2-12 alkynyl, with allowed alkynyl substituents including amino, —NH—C(=O)(unsubstituted C1-4 alkyl), hydroxy, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl options; R10A and R10B are selected from defined groups, and when R10A is an optionally substituted monocyclic C3-6 cycloalkyl(C1-4 alkyl), R10B cannot be an unsubstituted C2-6 alkenyl.
R9 substituted aromatic and heteroaromatic selection
R9 is a substituted phenyl, substituted monocyclic heteroaryl, or substituted fused-bicyclic heteroaryl, substituted with one or more of halogen, alkyl, cyano-substituted alkyl, haloalkyl, alkoxy, hydroxy-substituted alkoxy, monocyclic cycloalkyl, monocyclic heteroaryl, monocyclic heterocyclyl, amino, mono-substituted amine, di-substituted amine, and —C(=O)NHR11.
R11 substitution options
R11 is hydrogen, an unsubstituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C1-6 alkynyl, or an optionally substituted C3-6 monocyclic cycloalkyl.
Treatment method for hepatitis B
A method treats hepatitis B in a subject by administering an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject suffering from hepatitis B.
Overall, the claim coverage is grounded in the Formula (I) scaffold with coordinated substituent selections for Z1, R1, R2–R7, R8, R9, and R10A/R10B/R11. The coverage also includes a hepatitis B treatment method using the claimed compound.
Stated Advantages
The results are presented to indicate a wide therapeutic window for effective antiviral concentrations versus cytotoxicity.
Documented Applications
HBV-DNA antiviral testing in HepG2.117 cells with EC50/CC50 categorization for compounds of Formula (I).
Treating hepatitis B in a subject by administering an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition use for HBV/HDV treatment, including replication inhibition uses in connection with hepatitis B and hepatitis D.
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