Substituted cyanoindoline derivatives as NIK inhibitors
Inventors
Stansfield, Ian • Querolle, Olivier Alexis Georges • Poncelet, Virginie Sophie • Gross, Gerhard Max • Jacoby, Edgar • Meerpoel, Lieven • Kulagowski, Janusz Jozef • Macleod, Calum • MANN, Samuel Edward • Green, Simon Richard • Hynd, George
Assignees
Janssen Pharmaceutica NV • Janssen Cilag SAS • Argenta Discovery 2009 Ltd
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11180487-B2
Publication Date
2021-11-23
Expiration Date
Abstract
The present invention relates to pharmaceutical agents of formula (I) 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 compounds of Formula (I) as tautomers or stereoisomeric forms thereof, including pharmaceutically acceptable addition salts and solvates. The compound is defined by extensive substituent variables on the core scaffold, with multiple allowed chemical patterns across alkyl, halo, hydroxy, cyano, heterocyclyl, aryl, sulfonyl-like, and phosphonate-like options.
The structure further includes defined heterocyclyl units such as Het1a, Het1b, Het1c, Het1d, Het1e, Het1f, Het1g, Het2, Het3a, Het3b, Het4, Het5, Het6, Het7, and Het8, including specific ring sizes, heteroatom sets, and optional substitution patterns on ring N-atoms and ring C-atoms. Y is defined as CR4 or N, with R4 as hydrogen or halo, and R5 as halo, Het3a, —NR6aR6b, or —OR7, while R7 and related variables are constrained to listed substituent forms.
The disclosure also identifies selected specific compounds within the Formula (I) framework and covers their tautomers, stereoisomeric forms, pharmaceutically acceptable addition salts, and solvates. It also describes compounds and intermediates that support preparation of Formula (I) compounds, including numbered intermediates and associated characterized materials.
Claims Coverage
The consolidated claim coverage centers on one independent Formula (I) compound claim with extensive variable definitions and includes dependent refinements that fix particular substituent relationships, heterocycle selections, selected compounds, and pharmaceutical composition scope.
Compound of Formula (I) as tautomer or stereoisomeric form
A compound of Formula (I), wherein the compound is a tautomer or a stereoisomeric form, and wherein the substituent variables R1, R2, Y, R4, R5, R6a/R6b, R7, R8a/R8b, R9, R10, R11a/R11b, R12, R13, R14a/R14b/R14c/R14d, R15a/R15b, R16a/R16b, R17a/R17b, R18, R19a/R19b, R20a/R20b, and R21, together with the Het substituents, are constrained to the specified allowed definitions; the compound may be a pharmaceutically acceptable addition salt or a solvate thereof.
Defined heterocyclic substituent units
Het1a, Het1b, Het1c, Het1d, Het1e, Het1f, Het1g, Het2, Het3a, Het3b, Het4, Het5, Het6, Het7, and Het8 are defined as monocyclic or bicyclic heterocyclyl groups with specified ring sizes, heteroatoms, and optional substitution patterns; Het2 and certain Het3 groups are N-linked heterocyclyls of formula (b-1) or (c-1).
Phenyl and aromatic ring substitution control
R3 is phenyl optionally substituted with one, two or three substituents selected from the listed groups, R18 is a 5-membered aromatic ring containing one, two or three N-atoms optionally substituted with C1-4 alkyl and/or C3-6 cycloalkyl, and R21 is 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl with optional N-atom substitution.
Selected pictured compounds and their forms
The compound of Formula (I) is selected to include one of the pictured specific compounds and covers their tautomers, stereoisomeric forms, pharmaceutically acceptable addition salts, and solvates.
Pharmaceutical composition with a pharmaceutically acceptable carrier or diluent
A pharmaceutical composition includes a compound as claimed together with a pharmaceutically acceptable carrier or diluent.
Overall, the claim coverage is directed to a highly specified Formula (I) compound family with constrained substituent variables and defined heterocycle classes, and explicitly includes tautomers, stereoisomeric forms, pharmaceutically acceptable addition salts, and solvates. The dependent claims further specify selected compound forms and a pharmaceutical composition with a pharmaceutically acceptable carrier or diluent.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating or preventing cancers, including B-cell malignancies such as multiple myeloma, Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma [procedural detail omitted for safety].
Treating or preventing inflammatory disorders, including rheumatoid arthritis and COPD [procedural detail omitted for safety].
Treating or preventing metabolic disorders including obesity and diabetes [procedural detail omitted for safety].
Treating or preventing autoimmune disorders [procedural detail omitted for safety].
Interested in licensing this patent?