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-10899761-B2
Publication Date
2021-01-26
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
Heterocyclic bromodomain-modulating compounds are provided in forms according to Formula (I) and Formula (II), including pharmaceutically acceptable salts, solvates, tautomers, isomers, and deuterated analogs. The compounds modulate bromodomains, including inhibition of BET proteins and bromodomain proteins, and the disclosure states improved pharmacokinetic properties in the context of bromodomain activity.
The invention defines R1 substituent options and the presence of X when present, and describes a structural distinction versus WO 2014/145051 in which the di(pyridin-2-yl)methylene moiety includes a required R1 substituent. Pharmaceutical compositions are described comprising the heterocyclic bromodomain-modulating compounds and an effective amount for therapeutic treatment.
Methods are described for modulating bromodomains and for treating bromodomain-mediated diseases, including cancers, autoimmune/inflammatory disorders, tumor suppression contexts, viral infection-related inflammation including coronavirus, tumor cells, and synovial sarcoma. The disclosure also frames therapeutic use of bromodomain modulator compounds for combination therapy with multiple classes of anticancer agents, with cancer emphasized as a particular focus.
Claims Coverage
The independent claims provided cover four therapeutic methods. The inventive features center on administration of an effective amount of a compound of formula (II) with R1 defined as (C1–C3)alkyl, or administration of a compound of a specified formula, each as a pharmaceutically acceptable salt option.
Treating an inflammatory response to a viral infection with a formula (ii) compound having r1 as (c1–c3)alkyl
A method of treating an inflammatory response to a viral infection by administering to a subject in need an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, where R1 is (C1–C3)alkyl.
Treating an inflammatory response to a viral infection with a compound of a specified formula
A method of treating an inflammatory response to a viral infection by administering to a subject in need an effective amount of a compound of a specified formula, or a pharmaceutically acceptable salt thereof.
Treating synovial sarcoma with a formula (ii) compound having r1 as (c1–c3)alkyl
A method for treating synovial sarcoma by administering to a subject in need an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof, where R1 is (C1–C3)alkyl.
Treating synovial sarcoma with a compound of a specified formula
A method for treating synovial sarcoma by administering to a subject in need an effective amount of a compound of a specified formula, or a pharmaceutically acceptable salt thereof.
The independent claims cover therapeutic methods administering bromodomain-modulating compounds to treat inflammatory responses to viral infection and synovial sarcoma, with the claim sets distinguished by formula (II) with R1 as (C1–C3)alkyl versus a specified formula.
Stated Advantages
Improved pharmacokinetic (PK) properties.
Improved rat pharmacokinetics of compound P-001 versus a similar compound Z.
Stronger antitumor efficacy of P-001 versus Z in an IPC298 xenograft model.
Documented Applications
Treatment of bromodomain- or mutant-bromodomain-mediated diseases, with cancer emphasized.
Combination therapy for cancer using bromodomain modulator compounds with multiple classes of anticancer agents, described as synergistic.
GIST treatment using embodiments that include mutant c-Kit protein kinase inhibitor combinations.
Combination therapy with an FMS inhibitor (quizartinib or pexidartinib).
Treatment modalities and mechanistic classes referenced for combination include chemotherapies and epigenetic modulators (including HDAC inhibitors and DNMT inhibitors), as well as MEK and tyrosine kinase/EGFR/c-Kit mutant inhibitors.
Treating an inflammatory response to a viral infection, including coronavirus.
Treating synovial sarcoma.
Treating bromodomain-mediated diseases, including cancers, autoimmune/inflammatory disorders, viral infection-related inflammation including coronavirus, and tumor suppression contexts.
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