Heteroaromatic derivatives as NIK inhibitors
Inventors
Stansfield, Ian • Querolle, Olivier Alexis Georges • Ligny, Yannick Aime Eddy • Gross, Gerhard Max • Jacoby, Edgar • Meerpoel, Lieven • Green, Simon Richard • Hynd, George • Kulagowski, Janusz Jozef • Macleod, Calum • MANN, Samuel Edward
Assignees
Janssen Pharmaceutica NV • Janssen Cilag SAS • Argenta Discovery 2009 Ltd
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Publication Number
US-11136311-B2
Publication Date
2021-10-05
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 compounds of Formula (I), including tautomer or stereoisomeric forms thereof, and optionally pharmaceutically acceptable addition salts or solvates. The compounds are defined by multiple substituent variables, including R1, R2, Y, R4, R5, R6a/R6b, R7, R8a/R8b, R9, R10, and multiple Het and Ar groups, with specific allowed atom sets, substitution patterns, and attachment constraints.
Within Formula (I), R1 is C1-4 alkyl; R2 is C1-6 alkyl, C1-6 alkyl substituted with one R5, or C1-6 alkyl substituted with one, two or three fluoro atoms; Y is CR4; and R4 is hydrogen or halo. R5 is Het3a, —NR6aR6b, or —OR7, and the defined heteroatom-containing substituent options for R6a, R6b, and R7 further delimit the compound class.
A central structural feature is R3, which represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms independently selected from O, S, and N. This ring may be optionally substituted on one ring N-atom and on ring carbon atoms with defined sets, subject to stated attachment rules, and the structural scope further includes multiple heterocyclyl definitions with defined ring sizes, heteroatom content, and optional substitution patterns.
Claims Coverage
The provided material contains independent claim coverage directed to a compound of Formula (I) in tautomer or stereoisomeric form, with pharmaceutically acceptable addition salt or solvate coverage. The claim is built from multiple interconnected inventive structural features defined by substituent variables and heterocycle/heteroaromatic attachment rules.
Compound of formula (I) in tautomer or stereoisomeric form
A tautomer or stereoisomeric form of a compound of Formula (I), optionally as a pharmaceutically acceptable addition salt or a solvate thereof.
Defined substituent constraints for R1, R2, Y, R4, R5, R6a/R6b, and R7
R1 represents C1-4 alkyl; R2 represents C1-6 alkyl, C1-6 alkyl substituted with one R5, or C1-6 alkyl substituted with one, two or three fluoro atoms; Y represents CR4; R4 represents hydrogen or halo; R5 represents Het3a, —NR6aR6b, or —OR7; and R6a, R6b, and R7 are restricted to the listed hydrogen, alkyl, cycloalkyl, carbonyl-linked, sulfonyl-linked, phosphonate-linked, and heteroatom-containing options.
Substituted 5-membered heteroaromatic ring defined by R3
R3 represents a 5-membered heteroaromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N, with optional substitution on one ring N-atom and on ring carbon atoms by the enumerated substituent sets, together with the stated attachment constraint when Het1a or R18 are directly attached to the N-atom via a ring carbon atom.
Saturated heterocyclyl and N-linked heterocyclyl definitions
Het1a, Het1b, Het1c, Het1d, Het1e, Het1f, Het1g, Het2, Het3a, Het3b, Het4, Het5, Het6, and Het7 are defined as monocyclic or bicyclic saturated heterocyclyl or related heteroaryl/heterocycle groups with specified ring sizes, heteroatom composition, optional N-atom and ring carbon substitution, and ring attachment rules.
Claim coverage is centered on the broad Formula (I) compound class with tightly defined substituent variables, substituted heteroaromatic and heterocyclic ring systems, explicit attachment constraints, and optional salt/solvate forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A method of treating a selected B-cell malignancy in a warm-blooded animal by administering an effective amount of a compound as defined in the compound claim.
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