Substituted azaindoline derivatives as NIK inhibitors
Inventors
Hynd, George • Macleod, Calum • MANN, Samuel Edward • Kulagowski, Janusz Jozef • Stansfield, Ian • Querolle, Olivier Alexis Georges • Poncelet, Virginie Sophie • Gross, Gerhard Max • Jacoby, Edgar • Meerpoel, Lieven
Assignees
Janssen Pharmaceutica NV • Janssen Cilag SAS • Charles River Discovery Research Services UK Ltd
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11236084-B2
Publication Date
2022-02-01
Expiration Date
Abstract
The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
Core Innovation
The invention relates to substituted compounds of Formula (I), including a tautomer or a stereoisomeric form thereof, together with pharmaceutically acceptable addition salts or solvates. The structural scope defines multiple substituent variables and heterocycle groups, including Y as CR4 or N, R4 as hydrogen or halo, and R5 as halo, cyano, Het3a, —NR6aR6b, or —OR7.
Formula (I) further includes extensive definitions for R1, R2, R3, R6a, R6b, R7, Ar1, Ar2, and related substituent groups and ring systems. The disclosure also defines multiple heterocyclyl groups, including Het1a, Het1b, Het1c, Het1d, Het1e, Het1f, Het1g, Het2, Het3a, Het3b, Het4, Het5, Het6, Het7, and Het8, with ring-size ranges, saturation, heteroatom selection, and optional substitution patterns on ring N-atoms and ring C-atoms.
The documents further include pharmaceutical compositions, combination therapy, and treatment-related use context. Several items also describe synthetic examples, intermediates, and representative compounds within the Formula (I) series.
Claims Coverage
The consolidated claim coverage centers on a broad independent claim directed to a substituted compound of Formula (I), including tautomeric and stereoisomeric forms, with extensive substituent-variable definitions and heterocycle options. The combined claim set also includes dependent narrowing features and treatment or composition coverage. Overall, the claims present multiple inventive features focused on the Formula (I) scaffold and its defined substituents.
Substituted compound of Formula (I)
A compound of Formula (I), including a tautomer or a stereoisomeric form thereof, with multiple substituent variables defined by enumerated structural options.
Defined heterocycle and aromatic substituent frameworks
Multiple heterocycle groups, including Het1a/Het1b/Het1c/Het1d/Het1e/Het1f/Het1g/Het2/Het3a/Het3b/Het4/Het5/Het6/Het7/Het8, and aromatic groups such as R3, Ar1, and Ar2, with ring-size, heteroatom, and optional substitution limitations.
Y equals CR4 or N
In Formula (I), Y represents CR4 or N, with R4 representing hydrogen or halo.
R5 and associated substituent options
R5 represents halo, cyano, Het3a, —NR6aR6b, or —OR7, with further defined options for R6a, R6b, and R7.
Pharmaceutically acceptable addition salt or solvate
The compound of Formula (I) is also covered as a pharmaceutically acceptable addition salt, or a solvate thereof.
Treatment of a cell proliferative disease in a warm-blooded animal
A method for treating a cell proliferative disease in a warm-blooded animal by administering an effective amount of a pharmaceutical composition as described.
The consolidated claims define a broad Formula (I) compound family, with the main inventive scope arising from the permitted substituent-variable combinations, heterocycle and aromatic frameworks, and coverage of tautomeric, stereoisomeric, salt, and solvate forms. Additional claim content extends to pharmaceutical compositions and treatment-related use.
Stated Advantages
Inhibition of recombinant human NF-kappaB-inducing kinase (NIK/MAP3K14).
Assay-related activity affecting P-IKKα in L363 myeloma cells.
Documented Applications
Biochemical inhibition of recombinant human NF-kappaB-inducing kinase (NIK/MAP3K14) measured using biochemical kinase assay formats and AlphaScreen.
Cellular measurement of P-IKKα in L363 myeloma cells with IC50 values reported.
Inhibitors of NF-κB-inducing kinase (NIK/MAP3K14).
Prevention or treatment of cancer, inflammatory disorders, metabolic disorders, and autoimmune disorders, including obesity and diabetes, bone destruction in arthritis, and T-cell mediated autoimmunity including Graft Versus Host Disease (GVHD), as described.
Treatment of a cell proliferative disease in a warm-blooded animal by administering an effective amount of a pharmaceutical composition as described.
Interested in licensing this patent?