CK2 inhibitors, compositions and methods thereof
Inventors
Webber, Stephen E. • Tao, Xueliang • Brin, Elena
Assignees
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Publication Number
US-10227344-B2
Publication Date
2019-03-12
Expiration Date
Abstract
The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula (I), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof. For Formula (I) compounds R1, R2, R3, Ar and Z are as defined in the specification. The inventive Formula (I) compounds are inhibitors of CK2 and find utility in any number of therapeutic applications, including but not limited to treatment of proliferative disorders such as cancer, inflammation and immunological disorders.
Core Innovation
The invention relates to substituted pyrazolo[1,5-a]pyrimidine-3-carbonitrile compounds according to Formula (I), including stereoisomers, tautomers, and pharmaceutically acceptable salts. The structure is defined by variables Z, R1, R2, R3, R5, Ar, and R6, with Z as S(O) or S(O)2 and with substitution patterns on alkyl, alkenyl, alkynyl, haloalkyl, alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
The disclosed examples include methylsulfinylmethyl and methylsulfonylmethyl substituents, cyclopropylamino substitutions, and arylamino fragments such as pyridin-2-ylamino, pyridin-3-ylamino, aminopyridinyl, nitropyridinyl-derived aminopyridinyl forms, azetidine-, pyrrolidinyl-, piperidinyl-, and aminobutan-2-yl-substituted variants. The examples also include sulfoxide and sulfone forms and mono trifluoroacetic acid salt forms.
The compounds are identified as CK2 inhibitors, and the disclosure includes CK2 alpha inhibition assay evaluation and characterization data such as LC-MS, 1H NMR, HRMS, and melting point data. The document also references pharmaceutical compositions comprising a therapeutically effective amount of at least one Formula (I) compound with a pharmaceutically acceptable carrier, diluent, or excipient.
Claims Coverage
The provided claims collectively cover one Formula (I) compound class and a pharmaceutical composition. The recurring inventive features are the pyrazolo[1,5-a]pyrimidine-3-carbonitrile scaffold, the defined Z, R1, R2, R3, R5, Ar, and R6 variable sets, and dependent narrowing to specific substituent choices.
Formula (I) substituted pyrazolo[1,5-a]pyrimidine-3-carbonitrile compounds
A compound according to Formula (I), including stereoisomers, tautomers, and pharmaceutically acceptable salts, wherein Z is S(O) or S(O)2 and the substituents R1, R2, R3, R5, Ar, and R6 are defined by the claim variable definitions.
Z fixed to sulfone form
The compound according to Formula (I) in which Z is S(O)2.
R1 fixed to methyl
The compound according to Formula (I) in which R1 is methyl.
R6 constrained to cycloalkyl
The compound according to Formula (I) in which R6 is cycloalkyl.
Pharmaceutical composition formulation
A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to Formula (I), together with a pharmaceutically acceptable carrier, diluent, or excipient.
Overall, the claim coverage focuses on a Formula (I) substituted pyrazolo[1,5-a]pyrimidine-3-carbonitrile compound class with defined substituent variables and dependent narrowing features, together with pharmaceutical composition coverage.
Stated Advantages
Inhibitor compounds targeting CK2 are described for use against CK2-dependent diseases, including cancers and inflammatory/immunological disorders.
Documented Applications
CK2-dependent disease treatment is described, including cancers and inflammatory/immunological disorders, using CK2 inhibition by contacting CK2-overexpressing cells or by administering a compound to a mammal.
Biodistribution and receptor occupancy contexts are described using isotopically labeled compounds, including deuterium and PET isotopes.
Preparation and characterization of specific example compound classes, including TFA salts and sulfur-modified analogs, are documented.
Pharmaceutical compositions are described that include a therapeutically effective amount of a Formula (I) compound with pharmaceutically acceptable carrier, diluent, or excipient.
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