Heterocyclic compounds and uses thereof
Inventors
Ibrahim, Prabha N. • Spevak, Wayne • Zhang, Jiazhong • Shi, Songyuan • POWELL, BEN • Ma, Yan
Assignees
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Publication Number
US-12116365-B2
Publication Date
2024-10-15
Expiration Date
Abstract
Provided herein are heterocyclic compounds of Formula (I), pharmaceutical compositions containing such a compound and their therapeutic uses, methods for their preparation, intermediate compounds, pharmaceutical compositions containing such a compound, and their therapeutic uses.
Core Innovation
The patent describes methods for treating myelofibrosis by administering to a subject in need thereof an effective amount of a compound of Formula (I). The compound may be provided as a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog, and in Formula (I), R1 is cyano, halo, or a (C1-C3)alkyl optionally substituted with 1 to 3 substituents independently selected from halo, methyl, ethyl, methoxy, and ethoxy, and X, when present, is halo.
The disclosed compound class is evaluated through example comparisons of rat pharmacokinetics between Compound P-001 and a similar structural Compound Z referenced from WO 2014/145051. The patent reports improved rat PK exposure for Compound P-001 relative to Compound Z, and the examples also include xenograft efficacy and toxicity/toxicodynamics using IPC298, together with bromodomain-related bioassays for BRD2/3/4 binding, cell growth inhibition, and Myc reporter assay readouts.
The document connects the Formula (I) compounds to a therapeutic context for myelofibrosis and to pharmacological performance measures, including rat PK, xenograft efficacy/toxicity/toxicodynamics, and bromodomain bioassays. It also states a therapeutic combination framework in which myelofibrosis treatment is provided using the specified formula compound together with a kinase inhibitor.
Claims Coverage
The claim coverage includes 2 independent inventive features, both directed to myelofibrosis treatment. These features cover the Formula (I) compound definition with specified R1 and optional halo at X, and a separate combination treatment with a kinase inhibitor.
Formula (I) myelofibrosis treatment with R1 definition and halo substitution
A method for treating myelofibrosis comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, or deuterated analog thereof, where R1 is cyano, halo, or a (C1-C3)alkyl optionally substituted with 1 to 3 substituents selected from halo, methyl, ethyl, methoxy, and ethoxy, and where X, when present, is halo.
Combination myelofibrosis treatment with a kinase inhibitor
A method for treating myelofibrosis comprising administering an effective amount of a compound of a specified formula, or a pharmaceutically acceptable salt thereof, in combination with a kinase inhibitor.
Overall, the claims are directed to treating myelofibrosis using Formula (I) compounds defined by the R1 and X substitution pattern, and to a separate myelofibrosis treatment using a specified formula compound together with a kinase inhibitor.
Stated Advantages
Unexpectedly improved pharmacokinetics (PK) versus a structurally similar prior compound lacking the defined R1-substituted requirement.
Markedly improved rat PK exposure for Compound P-001 relative to Compound Z.
Strong tumor inhibition (TGI) in the reported xenograft model.
An improved toxicity profile for Compound P-001 versus Compound Z in the Ba/F3 toxicity model.
Documented Applications
Treatment of myelofibrosis by administering compounds of Formula (I), or variants, to a subject in need thereof.
Combination-therapy use for bromodomain- or mutant bromodomain-mediated conditions, including c-Kit mutant protein kinase inhibitor combinations for GIST and FMS inhibitor combinations using Table II compounds.
Rat pharmacokinetics comparison of Compound P-001 versus a similar structural Compound Z from WO 2014/145051.
IPC298 xenograft efficacy and toxicity/toxicodynamics comparison of P-001 and Z.
Bromodomain-related bioassays including Alphascreen BRD2/3/4 binding, cell growth inhibition in multiple oncology lines, and Myc reporter assay readouts.
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