RIP1 inhibitory compounds and methods for making and using the same

Inventors

Masuda, Esteban • Shaw, Simon • Taylor, Vanessa • Bhamidipati, Somasekhar

Assignees

Rigel Pharmaceuticals Inc

Abstract

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to treat or prevent a kinase-associated disease or condition, particularly a RIP1-associated disease or condition.

Core Innovation

The invention provides compounds, or pharmaceutically acceptable salts thereof, defined by a scaffold having ring B as a 5-membered heteroaryl. The scaffold includes a linker L equal to R_a, with the proviso that R_a is other than H or D, and a substituent R1 is defined as a linker-R6 group, where the linker is R_a and R6 is defined as R_b or —C(Rf)3.

The compounds further define substituents R2 and R3 independently as R_a, and define R4 and R5 independently as R_e. For each occurrence, R_a is independently H, D, or C1-10 aliphatic, while R_b is independently selected from —OH, —SH, —OR_c, —C(O)OR_c, —C(O)NR_dR_d, —SR_d, —NR_dR_d, or —C(O)OH, with R_c and R_d defined by allowed carbon, functional, heterocyclic, aryl, and heteroaryl structures and substitution limits, and R_e as independently selected halogen, C1-6 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C5-10 heteroaryl, or —OR_e.

The defined scaffold includes further occurrence parameters m, n, and p, with m being 1 to 4, n being 0, 1 or 2, and p being 0, 1, 2, 3, 4, or 5. The compounds inhibit RIP1, often selectively over RIP2/RIP3, and can be used for treating RIP1-associated diseases, with dependent-claim context also specifying oral treatment of rheumatoid arthritis. The examples and description include specific ring-B identities such as triazoles, oxadiazoles, and oxazoles, and mention stereoisomers and deuterium/isotopic variants, including prodrugs, solvates, salts, and compounds within tetrahydrobenzo[b][1,4]oxazepin triazole-carboxamide and related form sets.

Claims Coverage

The independent claim coverage centers on a compound defined by a Formula I/IA-style scaffold with ring B as a 5-membered heteroaryl, a linker L equal to R_a, and R1 as a linker-R6 group, together with occurrence ranges for m, n, and p. The inventive features combine the scaffold definition, linker constraints, and broad but specific substituent classes for R_a, R_b, R_c, R_d, R_e, and R_f.

The claim set is anchored by a scaffold in which ring B is a 5-membered heteroaryl, L is R_a with R_a not H or D, and R1 is a linker-R6 group with R6 as R_b or —C(Rf)3, together with defined substituent classes and occurrence limits. Dependent claims refine ring-B identity and substituent choices and include an oral treatment use for rheumatoid arthritis.

Stated Advantages

Documented Applications