JAK1 and ALK2 inhibitors and methods for their use

Inventors

Mollard, Alexis • Warner, Steven L. • Flynn, Gary A. • Vankayalapati, Hariprasad • Bearss, David J.

Assignees

Sumitomo Pharma Oncology Inc • Sumitomo Pharma America Inc

Abstract

Compounds having activity as inhibitors of ALK2 kinase and/or JAK2 kinase are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, z and A are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Core Innovation

The invention is directed to compounds of structure (I) and pharmaceutically acceptable salts thereof, together with related prodrugs, stereoisomers, tautomers, and pharmaceutically acceptable salts, centered on a defined core structure (I) and related structure (II), with extensive substituent and R-group definitions and provisos/exemplary embodiments. The disclosure includes a general reaction scheme for preparing compounds of the invention as final compounds of structure (I) from intermediates of structures (i)-(iv), and also mentions isotopically labeled compounds and metabolic product variants.

The disclosure further describes novel small-molecule ALK2 (ACVR1) and/or JAK2 kinase inhibitors and associates these kinase inhibitors with inhibition of ALK2 and/or JAK2 kinases. It explicitly links the inhibitors to treatment of cancer and anemia/anemia-related conditions and references hepcidin-related BMP/ALK2 pathway rationale, together with BMP signaling, type I BMP receptors, SMAD proteins, and ferroportin.

The document further describes pharmaceutical compositions comprising the ALK2 (ACVR1) and/or JAK2 inhibitors. It also includes multiple chemical structure depictions for specific compound candidates labeled EMI-C00017 through EMI-C00040 and notes that Table 1 provides exemplary compounds with JAK2/ALK2 activity.

Claims Coverage

The independent claims include one method claim directed to treating a selected solid tumor by administering an effective amount of a compound having a specified structure or a pharmaceutically acceptable salt. The inventive concept centers on the compound structure defining ALK2 (ACVR1) and/or JAK2 inhibition for oncology use, with dependent refinements focused on tumor type, salt form, and combination administration with chemotherapeutic agents.

Overall, the claim coverage centers on administering an effective amount of a compound having the specified structure, or a pharmaceutically acceptable salt, to treat defined solid tumors, with further limitations to particular cancers, acid addition salt forms, and combination administration with one or more chemotherapeutic agents.

Stated Advantages

Documented Applications