6-membered heteroaromatic substituted cyanoindoline derivatives as NIK inhibitors
Inventors
Stansfield, Ian • Querolle, Olivier Alexis Georges • 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
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Publication Number
US-11001569-B2
Publication Date
2021-05-11
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 a cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
Core Innovation
The invention concerns compounds defined by Formula (I), including tautomeric and stereoisomeric forms, together with pharmaceutically acceptable addition salts and solvates. The Formula (I) scaffold is defined by variable substituents and heteroaromatic and heterocyclyl groups, including R1, R2, Y, R4, R5, R6a, R6b, R7, R8a, R8b, R9, R10, R11a, R11b, R12, R13, R14a, R14c, R14d, R15a, R15b, R17a, R17b, R18, R19a, R19b, R21, Het1a, Het1b, Het1c, Het1d, Het2, Het3a, and Het3b, with bounded substitution patterns on ring carbon atoms and N-atoms.
Within Formula (I), Y represents CR4 or N, R4 represents hydrogen or halo, and R5 represents Het3a, —NR6aR6b, or —OR7. The scaffold includes 6-membered heteroaromatic rings containing 1 or 2 N-atoms, a 2-oxo-1,2-dihydropyridin-3-yl option for R3, and N-linked 4- to 7-membered monocyclic saturated heterocyclyl groups with defined substitution constraints. The definitions also include options for alkyl, halo, cyano, alkoxy, cycloalkyl, carbonyl-containing groups, and defined variants such as R21 as 3,6-dihydro-2H-pyran-4-yl.
The claim set further associates the Formula (I) compounds with pharmaceutical compositions and therapeutic use. The provided content includes a pharmaceutical composition comprising a compound of Formula (I) together with a pharmaceutically acceptable carrier or diluent, and treatment of B-cell malignancies in warm-blooded animals by administering an effective amount of the compound, with multiple myeloma, Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia identified.
Claims Coverage
The consolidated claim coverage centers on a broad Formula (I) compound family with explicit tautomeric and stereoisomeric forms, together with pharmaceutically acceptable addition salts and solvates. In total, the independent claims cover the Formula (I) chemical space and its defined formal variants, and related claims extend to pharmaceutical composition and therapeutic-use subject matter.
Formula (I) compound scaffold with tautomer or stereoisomeric forms
A compound of Formula (I), wherein the compound is a tautomer or a stereoisomeric form thereof, with R1, R2, Y, R4, R5, R6a, R6b, R7, and the remaining ring and substituent variables defined by the specified structural options.
Defined heteroaromatic and heterocyclyl substituent framework
R3 represents a 6-membered heteroaromatic ring containing 1 or 2 N-atoms or a 2-oxo-1,2-dihydropyridin-3-yl option, and Het1a, Het1b, Het1c, Het1d, Het2, Het3a, and Het3b are defined as N-linked 4- to 7-membered monocyclic saturated heterocyclyl or related heterocyclyl structures with specified substitution rules.
Heteroatom-linked substituent selection for R5 and R7
R5 represents Het3a, —NR6aR6b, or —OR7, with R6a and R6b limited to the defined hydrogen, alkyl, cycloalkyl, carbonyl-containing, or substituted alkyl options, and R7 limited to the defined hydrogen, C1-4 alkyl, amine-containing, carbonyl-containing, or C1-4 alkyl-Het3b options.
Pharmaceutically acceptable addition salt or solvate
The Formula (I) compound is included as a pharmaceutically acceptable addition salt or a solvate thereof.
Pharmaceutical composition comprising a Formula (I) compound
A pharmaceutical composition comprising a compound of Formula (I) together with a pharmaceutically acceptable carrier or diluent.
Treatment of B-cell malignancy in warm-blooded animals
A method of treating a B-cell malignancy in a warm-blooded animal by administering an effective amount of the compound, with the malignancy selected from multiple myeloma, Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukemia.
The independent claim scope is concentrated on a broad Formula (I) compound family with tightly defined R-group and heterocycle selections, including tautomeric and stereoisomeric forms and pharmaceutically acceptable addition salts and solvates. The claim set also includes a pharmaceutical composition and a therapeutic method directed to specified B-cell malignancies in warm-blooded animals.
Stated Advantages
NF-κB inducing kinase (NIK/MAP3K14) inhibition.
Therapeutic indications described for cancer and inflammatory/metabolic/autoimmune disorders.
Therapeutic treatment of B-cell malignancies, including multiple myeloma, in warm-blooded animals.
Documented Applications
Inhibition of NF-κB inducing kinase (NIK/MAP3K14) for therapeutic use.
Methods of treatment for cancer and inflammatory/metabolic/autoimmune disorders using the described compounds.
Treatment of B-cell malignancies in warm-blooded animals, including multiple myeloma, Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia.
Use in a pharmaceutical composition comprising a compound of Formula (I) with a pharmaceutically acceptable carrier or diluent.
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