SIK inhibitors

Inventors

Bootsma, Andrea Nicole • Ebner, David Christopher • KUNG, DANIEL WEI-SHUNG • Perry, Matthew Alexander • Schmitt, Daniel Copley • Strohbach, Joseph Walter • Thorarensen, Atli

Assignees

Pfizer Inc

Abstract

A compound of formula I having the structure: or a pharmaceutically acceptable salt thereof, wherein A1 and A2 are independently O or S; X is selected from CH2, CD2, NR3, O, and S, where R3 is selected from hydrogen, C1-C4 linear or branched chain alkyl, halo(C1-C4)linear or branched chain alkyl, and hydroxyl(C1-C4)linear or branched chain alkyl; Y and Z are selected from C and N, where when Y is C, then Z is N, and when Y is N, then Z is C; R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 linear or branched chain alkyl, etc.; or a C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or taken together to form a C3-C6 cycloalkyl ring; or where X is CH2 or CD2, then R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 linear or branched chain alkyl, etc.; R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, etc.; R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 linear or branched chain alkyl)amino, etc.; R6 is selected from hydrogen, deuterium, halogen, CO2R7 where R7 is selected from H and C1-C4 linear or branched chain alkyl, etc.; R8 is selected from hydrogen, deuterium, and C1-C3 linear or branched chain alkyl; R9 is selected from C1-C3 linear or branched chain alkyl, and a halo(C1-C3)linear or branched chain alkyl; and, n and m are independently selected from 0, 1 and 2. The invention also relates to pharmaceutical compositions thereof and therapeutic methods of use therewith.

Core Innovation

The patent describes formula IA benzonitrile derivatives, including imidazo[1,2-a]pyridine-5-carbonitrile derivatives, and pharmaceutically acceptable salts thereof as SIK1, SIK2, and SIK3 modulators. The compounds have defined alternatives for scaffold atoms, substituents, and ring-size parameters. The disclosure also identifies narrower embodiments and specified compounds, and describes pharmaceutical compositions containing a compound or salt with an excipient.

The described therapeutic use includes inflammatory and autoimmune conditions, especially inflammatory bowel disease and ulcerative colitis, as well as Crohn's disease. Reaction Schemes IA–IV are identified as general preparation routes for the compound series. The background section is not included in the provided text, so the underlying technical problem is not explicitly described.

The disclosure reports activity across examples in salt-inducible kinase enzyme assays and human monocyte-derived macrophage assays, including measurements for SIK1, SIK2, SIK3, TNFα, and IL-10. Examples 45 and 53 are identified among the most potent examples in the reported data.

Claims Coverage

The claims identify six inventive features: a formula IA compound genus and five specified compounds, each including pharmaceutically acceptable salts. One input lists only claim 1 and claims 18 through 21 (four specified compounds), while another also lists the aminocyclohexyl compound.

The independent claims cover a variable formula IA compound genus and specifically named compounds, each including pharmaceutically acceptable salts. Additional claim coverage identifies narrower substituent embodiments and a pharmaceutical composition containing a claimed compound or salt or solvate with a pharmaceutically acceptable excipient.

Stated Advantages

Documented Applications