RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
Inventors
Lançois, David Francis Alain • Guillemont, Jérôme Émile Georges • Raboisson, Pierre Jean-Marie Bernard • Roymans, Dirk André Emmy • Rogovoy, Boris • Bichko, Vadim • Lardeau, Delphine Yvonne Raymonde • Michaut, Antoine Benjamin • Koul, Anil
Assignees
Chemdiv Inc • Janssen Pharmaceutica NV • Janssen Cilag SAS • Novalix SAS • Janssen Sciences Ireland ULC
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Publication Number
US-10208048-B2
Publication Date
2019-02-19
Expiration Date
Abstract
The invention concerns novel substituted pyrazolo- and triazolo-pyrimidine compounds of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment of respiratory syncytial virus infection.
Core Innovation
The disclosure concerns compounds of formula (I) and any stereochemically isomeric form thereof, including pharmaceutically acceptable acid addition salts. The compounds are defined by a structural framework with variable substituents, including X as N or CR6, R1 as CH3 or CH2CH3 with R1' as hydrogen or a cyclopropyl-forming option, and R2 and R3 as specified alkyl groups.
The moiety of formula (I) includes a radical framework with extensive allowed selections for R4 and R5, together with enumerated heteroaryl, heterocycle, aryl, bicycle, and spiro[3.3]heptanyl-related options. Radical (a-1) to (a-30) are optionally substituted with one or two substituents each independently selected from C1-2 alkyl and halo, and additional branches define substituent selections for NR7R8 and related carbonyl, thiocarbonyl, sulfonyl, and ring-containing groups.
The disclosure also positions the invention as addressing respiratory syncytial virus infection and an unmet need for non-toxic, easy-to-administer RSV replication inhibitors. The document includes pharmaceutical composition coverage using a pharmaceutically acceptable carrier and a therapeutically active amount, and reports antiviral and cytotoxicity data in a cell-based system for exemplified compounds.
Claims Coverage
The consolidated claim coverage centers on a broad independent claim defining a compound of formula (I) and any stereochemically isomeric form thereof, together with pharmaceutically acceptable acid addition salts. The claim uses multiple structural feature groups, including X/R6, R1/R1' with an optional cyclopropyl form, R2/R3 alkyl constraints, a radical framework with optional substitution, and extensive permitted classes for R4, R5, and related heteroaryl/heterocycle/aryl/bicycle options.
Compound of formula (I) with stereochemically isomeric forms
A compound of formula (I) and any stereochemically isomeric form thereof, including pharmaceutically acceptable acid addition salts.
X, R1, R1' and alkyl substitution constraints
X is N or CR6, where R6 is hydrogen, halo or C1-4 alkyl; R1 is CH3 or CH2CH3 and R1' is hydrogen, or R1 and R1' are taken together with the carbon atom to which they are attached to form cyclopropyl; and R2 is C3-6 alkyl and R3 is C1-4 alkyl.
Radical moiety with optional substitution
The moiety is a radical of a defined formula, and radical (a-1) to (a-30) are optionally substituted with one or two substituents each independently selected from C1-2 alkyl and halo.
Defined R4, R5, heteroaryl, heterocycle, aryl and bicycle options
R4 and R5 are defined by extensive lists of permitted substituent classes, including C1-6 alkyl, C3-6 alkenyl, polyhaloC1-4 alkyl, cycloalkyl, aminocarbonyl, oxetanyl, heteroaryl, heterocycle, aryl, bicycle, and related substituted variants, with enumerated heteroaryl, heterocycle, aryl, and bicycle ring systems.
Exclusion of two specified compounds
The claim excludes [7-ethyl-2-(3-thienyl)pyrazolo[1,5-a]pyrimidin-5-yl] (2-methyl-1-piperidinyl)-methanone and [7-ethyl-2-(2-pyridinyl)pyrazolo[1,5-a]pyrimidin-5-yl](2-methyl-1-piperidinyl)-methanone.
The claim coverage is a broad genus of formula (I) compounds with stereochemical isomer coverage, defined substituent constraints for X/R6 and R1/R1', fixed alkyl limits for R2 and R3, and a large enumerated framework for the remaining substituent classes. It also includes pharmaceutically acceptable acid addition salts and explicitly excludes two named methanone compounds.
Stated Advantages
Non-toxic.
Easy-to-administer.
RSV replication inhibitor activity is positioned to address respiratory syncytial virus infection.
Documented Applications
Use of the compounds as RSV replication inhibitors for respiratory syncytial virus infection.
Pharmaceutical composition with a pharmaceutically acceptable carrier and a therapeutically active amount.
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