Compounds as inhibitors of AXL

Inventors

BEATTY, Joel Worley • FOLEY, Corinne Nicole • GAL, Balint • Lamani, Manjunath • Leleti, Manmohan Reddy • MILES, Dillon Harding • Paladugu, Srinivas • Powers, Jay Patrick • Qu, Shiwei

Assignees

Arcus Biosciences Inc

Abstract

Compounds of Formula I that inhibit AXL, and compositions containing the compound(s) and methods for synthesizing the compounds, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer, that are mediated, at least in part, by AXL.

Core Innovation

The disclosure relates to compounds having the structure of Formula (I) and Formula (B-3), and to pharmaceutically acceptable salts, hydrates, and solvates of the compound. Multiple substituent-variation embodiments are specified for the Formula (I) structure, with definitional ranges and classes for substituents including p, R1, R1a, R2, R3, R4, X, G1-G5, and fused ring A, together with alternative core formula depictions and structured embodiments through the defined mapping of A/R2 and the substituent framework.

The disclosure also relates to AXL, a TAM-family receptor tyrosine kinase, and frames the invention around inhibiting AXL activity for treatment of AXL-mediated conditions. The core invention provides compounds according to Formula (I), including variable substituent parameters and a fused ring A, and includes pharmaceutical compositions comprising the Formula (I) compounds and pharmaceutically acceptable salts. The document characterizes disease-relevant signaling pathways, including the RAS-RAF-MEK-ERK pathway and the PI3K/AKT pathway, in which AXL is involved.

The patent further describes substituted pyrazolo[3,4-b]pyridine, pyrrolo[2,3-b]pyridine, and benzo[7]annulene-based scaffolds, including substituted 7S stereospecific polycyclic heteroaromatic compounds in which a tetrahydro-benzo[7]annulen fused system is retained. The disclosed structures include appended substituted rings and substituent patterns such as methyl, fluoro, difluoromethyl, difluoromethoxy, and trifluoromethyl groups, and the examples are accompanied by 1H NMR and ESI MS characterization, including calculated versus found masses.

Claims Coverage

The provided independent claims are directed to compounds defined by chemical structure, with pharmaceutically acceptable salts in some excerpts. Across the input items, the extracted claim coverage centers on structurally defined compounds, including Formula (I) compounds, compounds having the structure, and compounds having the structure or a pharmaceutically acceptable salt thereof.

The claim coverage is consistently directed to compounds defined by a particular chemical structure, with pharmaceutically acceptable salts expressly included in several excerpts. No additional independent-claim inventive features beyond the structure-directed coverage are explicitly extractable from the provided claim text.

Stated Advantages

Documented Applications