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Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor–associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys(63)-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6–Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6–Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6–Ubc13 interaction that reduces TRAF6–Ubc13 activity both in vitro and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical in vivo mouse models. Hence, the first-in-class TRAF6–Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.

Unsymmetric, N-substituted benzimidazoles and imidazopyridines can be prepared directly from 2-halonitroarenes and amides through Pd(TFA) 2 /(R)-BINAP-catalyzed cross-coupling and subsequent reductive aminocyclization. This sequence can be conducted by a one-pot procedure. The method is versatile and allows the straightforward, regioselective preparation of these important nitrogen heterocycles.

The present new general palladium-catalyzed procedure for the cross-coupling of (hetero)aryl tosylates provides a facile access to various functionalized (hetero)aryl alkynes tolerating many functional groups.

4,5-Dialkynyl-2-(methyl or phenyl)-3(2H)-pyridazinones (2a–c) were efficiently prepared via Sonogashira cross-coupling reaction on 4,5-dichloro-2-(methyl or phenyl)-3(2H)-pyridazinones (1a,b). Selective Sonogashira reactions were successfully achieved on 4-chloro-2-methyl-5-trifluoromethanesulfonyloxy- (6) and 5-chloro-2-methyl-4-trifluoromethanesulfonyloxy-3(2H)-pyridazinone (11), yielding 5-alkynyl-4-chloro- (7a–c) and 4-alkynyl-5-chloro-2-methyl-3(2H)-pyridazinones (3a,c,e), respectively. Compounds 7a–c and 3a,c,e were subjected to a second Sonogashira reaction giving 4,5-dialkynyl-2-methyl-3(2H)-pyridazinones (8a–c) bearing two different acetylene substituents. Suzuki cross-coupling reaction was also achieved on compounds 7a and 3a producing 4-aryl-5-phenylethynyl- and 5-aryl-4-phenylethynyl-2-methyl-3(2H)-pyridazinones, respectively, in excellent yield.

The synthesis of 4-aryl-5-methoxy-, 5-aryl-4-methoxy- and 4,5-diaryl-3(2H)-pyridazinones via Suzuki palladium-catalysed cross-coupling reactions with the corresponding chloro-3(2H)-pyridazinones is described.

A versatile and efficient palladium catalyzed domino reaction leading to a broad range of substituted 1-aminoindoles has been developed. The title compounds were prepared from 2-halo-phenylacetylenes and simple hydrazines in good to excellent yields in just a few hours under mild conditions.

A sequential Pd-catalyzed amidation—Fe-mediated reductive aminocyclization of o-chloronitro(het)arenes with aromatic or aliphatic amides provides an efficient access towards benzimidazole derivatives.

The present new general palladium-catalyzed procedure for the cross-coupling of (hetero)aryl tosylates provides a facile access to various functionalized (hetero)aryl alkynes tolerating many functional groups.

A versatile and efficient palladium catalyzed domino reaction leading to a broad range of substituted 1-aminoindoles has been developed. The title compounds were prepared from 2-halo-phenylacetylenes and simple hydrazines in good to excellent yields in just a few hours under mild conditions.

The synthesis of 4-aryl-5-methoxy-, 5-aryl-4-methoxy- and 4,5-diaryl-3(2H)-pyridazinones via Suzuki palladium-catalysed cross-coupling reactions with the corresponding chloro-3(2H)-pyridazinones is described.

4,5-Dialkynyl-2-(methyl or phenyl)-3(2H)-pyridazinones (2a–c) were efficiently prepared via Sonogashira cross-coupling reaction on 4,5-dichloro-2-(methyl or phenyl)-3(2H)-pyridazinones (1a,b). Selective Sonogashira reactions were successfully achieved on 4-chloro-2-methyl-5-trifluoromethanesulfonyloxy- (6) and 5-chloro-2-methyl-4-trifluoromethanesulfonyloxy-3(2H)-pyridazinone (11), yielding 5-alkynyl-4-chloro- (7a–c) and 4-alkynyl-5-chloro-2-methyl-3(2H)-pyridazinones (3a,c,e), respectively. Compounds 7a–c and 3a,c,e were subjected to a second Sonogashira reaction giving 4,5-dialkynyl-2-methyl-3(2H)-pyridazinones (8a–c) bearing two different acetylene substituents. Suzuki cross-coupling reaction was also achieved on compounds 7a and 3a producing 4-aryl-5-phenylethynyl- and 5-aryl-4-phenylethynyl-2-methyl-3(2H)-pyridazinones, respectively, in excellent yield.

A new synthetic route towards the synthesis of 1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-ones (10a-f) and their regioisomers 1,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-ones (9a,b) is described, based on the reaction of 5-alkynyl-4-chloro- (7a,b) and 4-alkynyl-5-chloropyridazinones (8) with different amines (ammonia, methylamine and propylamine) followed by a treatment with a NaOEt solution.

A study of the reactivity of 5-alkynyl-4-chloro- (la,b) and 4-alkynyl-5-chloropyridazin-3(2H)-ones (4a,b) towards oxygen and sulfur nucleophiles (NaOCH 3 , NaSCH 3 , KOH and Na 2 S) is reported. The synthesis of 5-alkynyl-2-methyl-4-methoxy- (2a,b) and 5-alkynyl-2-methyl-4-methylthiopyridazin-3(2H)-ones (3a,b) and their regioisomers 4-alkynyl-2-methyl-5-methoxy- (5a,b) and 4-alkynyl-2-methyl-5-methylthiopyridazin-3(2H)-ones (6a,b) is described, as well as the synthesis of 2-substituted 6-methylfuro[2,3-d]- (7a,b,c) and 2-substituted 6-methylthieno[2,3-d]pyridazin-7(6H)-ones (8a,b) and their regioisomers 2-substituted 5-methylfuro[2,3-d]- (9a,b,c) and 2-substituted 5-methylthieno[2,3-d]pyridazin-4(5H)-ones (10a,b).