Pyrazole derivatives as MALT1 inhibitors
Inventors
Lu, Tianbao • Connolly, Peter J. • Cummings, Maxwell David • Diels, Gaston Stanislas Marcella • Thuring, Jan Willem • Philippar, Ulrike • Edwards, James Patrick • Berthelot, Didier Jean-Claude • Wu, Tongfei
Assignees
Janssen Pharmaceutica NV • Janssen Cilag SAS • Janssen Research and Development LLC
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Publication Number
US-10888550-B2
Publication Date
2021-01-12
Expiration Date
Abstract
Disclosed are compounds, compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the modulation of MALT1. Such compounds are represented by Formula (I) as follows: wherein R1, R2, R3, R4, R5, R6, R7, G1 and G2, are defined herein.
Core Innovation
The invention relates to substituted heteroaromatic carboxamide compounds that are MALT1 inhibitors, including pyrazole-, imidazo[1,2-a]pyridine-, and pyrazolo[1,5-a]pyridine-type cores. The compounds include defined substituent patterns with triazolyl, oxazolyl, pyrazolyl, methylsulfonyl, fluoro, chloro, cyano, trifluoromethyl, methyl, and ethyl substituents, and further include enantiomers, diastereomers, solvates, and pharmaceutically acceptable salt forms.
The disclosure states that MALT1 is a mediator of classical NF-κB signaling downstream of the CBM complex, including CARD11 and BCL10, and that targeting MALT1 protease activity is a therapeutic approach. The document situates MALT1 inhibition within cancer signaling and immune-related signaling and references API2-MALT1.
The disclosure also identifies specific MALT1 inhibitor candidate compounds and related analogs, and provides biochemical and cellular assessment frameworks. It reports MALT1 biochemical protease activity evaluation and cellular readouts including IL-2 and IL-6/IL-10 measurements, together with compound preparation and characterization for selected structures.
Claims Coverage
The independent claim coverage is directed to an independently selected compound from a defined group of substituted heteroaromatic carboxamides, with 4 inventive features identified across the combined inputs. The claim scope includes fused heteroaromatic carboxamide scaffolds, defined substituent patterns, stereochemical forms, and pharmaceutically acceptable salt forms.
Substituted heteroaromatic carboxamide compounds
An independently selected compound from a defined group of substituted heteroaromatic carboxamides, including imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, and related pyrazole carboxamide structures.
Defined heteroaryl substituents and substituted ring patterns
The selected compounds include triazolyl, oxazolyl, pyrazolyl, methylimidazolyl, methylsulfonyl, fluoro, chloro, cyano, and trifluoromethyl substituents, with related fused-ring variants.
Stereochemical and salt form coverage
The compounds include enantiomers, diastereomers, solvates, and pharmaceutically acceptable salt forms, including explicitly stated (*R) and (*S) variants.
Dimethyl(oxo)-λ6-sulfanylidene amino substituted variants
Selected compounds include dimethyl(oxo)-λ6-sulfanylidene amino substituted pyrazole carboxamide variants and related substitution patterns.
The claim coverage is directed to a defined set of substituted heteroaromatic carboxamides with pyrazole, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyridine cores, specified heteroaryl and halogenated substitutions, and explicit stereochemical and pharmaceutically acceptable salt coverage.
Stated Advantages
MALT1 inhibition is presented as a therapeutic approach for preventing or treating disease in warm-blooded animals, including humans.
Targeting MALT1 protease activity is presented in the context of cancer signaling and immune-related signaling.
Documented Applications
Preventing or treating diseases in warm-blooded animals, including humans, using the Formula (I) compounds and related enantiomers, diastereomers, solvates, and pharmaceutically acceptable salts.
Treatment of cancer and immunological and autoimmune diseases, with particular emphasis on ABC-DLBCL and DLBCL.
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