Rigel Pharmaceuticals, Inc.

Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions. In certain embodiments, the compounds have Formula IIa or IIb:

Solid forms of 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate, solid forms of salts thereof, including solid forms comprising 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate monosodium salt, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed.

Disclosed herein are methods for treating, managing, or ameliorating a disease selected from myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), MPN/MDS, clonal cytopenia of undetermined significance (CCUS), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). The methods comprise administering to a subject in need thereof a therapeutically effective amount of 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate or a stereoisomer or mixture of stereoisomers, a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

Provided herein is a pharmaceutical composition comprising 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate or a pharmaceutically acceptable salt thereof as an active agent, one or more intragranular excipients and one or more extragranular excipients.

Disclosed herein are embodiments of a method for treating a disease or condition in a subject, comprising administering to the subject, a pyrazole compound according to formula I. The compound may be administered as a composition, such as a spray-dried formulation. The disease or condition may be hidradenitis suppurativa, or a lymphoid neoplasm, and may be chronic myeloid leukemia or chronic myelomonocytic leukemia.

The compound cis)-N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4 methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide can be prepared as a free base in various crystalline solid forms, and in various salt forms each having one or more solid forms.

Disclosed herein are methods for treating a subject afflicted with a cancer having an activating RET alteration by administering an effective amount of a selective RET inhibitor, e.g., Compound 1 or pharmaceutically acceptable salts thereof, including, e.g., administering an amount of 60 mg to 400 mg of the selective RET inhibitor once daily.

Disclosed embodiments concern compounds according to Formula I In some embodiments, the compounds are useful as kinase inhibitors, such as interleukin receptor associated kinases (IRAK) inhibitors. Also disclosed are compositions comprising such inhibitors, and methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent a kinase-associated disease or condition, particularly an IRAK-associated disease or condition.

Disclosed embodiments concern novel interleukin receptor associated kinases (IRAK) inhibitor compounds and compositions comprising such compounds. The compounds may have a structure according to Formula I Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

Disclosed embodiments concern novel interleukin receptor associated kinases (IRAK) inhibitors and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.