PTPN11 inhibitors
Inventors
Jones, Philip • Czako, Barbara • Carroll, Christopher L • MANDAL, Pijus • Cross, Jason
Assignees
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Publication Number
US-11945815-B2
Publication Date
2024-04-02
Expiration Date
Abstract
The present invention relates to compounds which are useful as inhibitors of PTPN11 for the treatment or prevention of cancer and other PTP-mediated diseases. Disclosed herein are new compounds and compounds based on pyrazolopyrazines and their application as pharmaceuticals for the treatment of disease.
Core Innovation
The disclosure provides chemical structures for compounds represented by Formula I, Formula Ia-Ic, Formula II, and later Formulae II-XI, with explicit variable definitions for substituents within those formulae. The chemical structure definitions include salts, esters, prodrugs, conformational isomers, and tautomers, and the compounds are supported by extensive formula listings and structural depictions.
The compounds are described as pyrimidinone core compounds and substituted pyrimidin-4(3H)-one derivatives, including representative structures with aryl substituents and multiple halogenated phenyl, pyridyl, or pyrimidinyl groups. Specific compound structures and illustrative examples are presented, together with characterization information such as MS and NMR.
A central aspect of the invention is that the Formula I compounds are characterized by their ability to inhibit PTPN11 (SHP2) activity. The compounds and pharmaceutically acceptable salts are positioned for use in treatment settings involving PTPN11-mediated diseases, with pharmaceutical compositions comprising a pharmaceutically acceptable carrier.
Claims Coverage
The independent claims cover formula-defined compounds, pharmaceutically acceptable salts, pharmaceutical compositions with a pharmaceutically acceptable carrier, and method-of-treatment claims for specified cancers. In total, the claim coverage includes multiple inventive features across structural compound and salt claims and therapeutic use claims, with cancer subtypes such as lung cancer and colon cancer specifically recited in the independent method claims.
Formula-defined compound
A compound represented by the formula.
Pharmaceutically acceptable salt of a formula-defined compound
A pharmaceutically acceptable salt of a compound, wherein the compound is represented by the formula.
Pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound represented by the formula together with a pharmaceutically acceptable carrier.
Treatment of PTPN11-mediated cancer using a formula-defined compound
Treating a PTPN11-mediated cancer in a patient by administering a therapeutically effective amount of the compound represented by the formula, where the cancer is selected from breast cancer, colon cancer, lung cancer, esophageal cancer, gastric cancer, leukemia, or melanoma.
Treatment of PTPN11-mediated cancer using a pharmaceutically acceptable salt
A method of treatment of a PTPN11-mediated disease by administering a therapeutically effective amount of a pharmaceutically acceptable salt of the compound represented by the formula to a patient, where the disease is cancer selected from breast cancer, colon cancer, lung cancer, esophageal cancer, gastric cancer, leukemia, or melanoma.
Lung cancer treatment
A method of treatment of lung cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by the formula or a pharmaceutically acceptable salt thereof.
Colon cancer treatment
A method of treatment of colon cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound represented by the formula or a pharmaceutically acceptable salt thereof.
The claims provide structural coverage through formula-based definitions of compounds and pharmaceutically acceptable salts, together with pharmaceutical compositions using a pharmaceutically acceptable carrier. Therapeutic coverage applies these compounds and salts to PTPN11-mediated cancers, with further independent claim coverage directed to lung cancer and colon cancer.
Stated Advantages
PTPN11 inhibitor activity is described via enzymatic IC50 thresholds and phospho-ERK target engagement assay results.
Treating PTPN11-mediated cancers, including leukemia, melanoma, and cancers of breast, lung, and colon.
In vivo tumor growth inhibition outcomes are reported in NSG and KYSE520 xenograft models for selected examples.
Documented Applications
Treating PTPN11-mediated cancers in a patient using a therapeutically effective amount of a formula-defined compound or a pharmaceutically acceptable salt.
Lung cancer treatment of a patient, with a dependent refinement to non-small cell lung cancer.
Colon cancer treatment of a patient, with a dependent refinement to colorectal cancer.
Biological assay contexts supporting PTPN11 inhibitor activity, including a PTPN11 enzymatic assay, a phospho-ERK target engagement assay, and a colony formation assay for selected examples.
In vivo xenograft use in NSG and KYSE520 xenograft models with reported tumor growth inhibition for selected examples.
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