Pyrazolo[1,5-a]pyridines as p38 Kinase Inhibitors

Abstract

[reaction: see text] A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved either via a regioselective [3 + 2] cycloaddition of N-aminopyridines with alkynes or by thermal cyclization of disubstituted azirines. Subsequent palladium-catalyzed introduction of pyridines or de novo synthesis of pyrimidines affords inhibitors of p38 kinase.

Oligosubstituted Pyrroles Directly from Substituted Methyl Isocyanides and Acetylenes

“…The prepared derivatives can also be easily transformed into pyrroles of higher or lower order of substitution according to established protocols. [30,31] Experimental Section Starting materials: Methyl cyclopropylpropiolate (2 a), [32] tert-butyl cyclopropylpropiolate (2 b), [33] 4-nitrophenylmethyl isocyanide (1 g), [34] cyanomethyl isocyanide (1 d), [35] diethyl (3-methoxyprop-1-ynyl)phosphonate (2 d), [36] ethyl trifluoromethylpropiolate (2 e), [37] methyl morpholin-4-ylpropiolate (2 f), [38] methyl 3-(4-fluorophenyl)propiolate (2 i), [39] methyl 3-(4-trifluoromethylphenyl)propiolate (2 j), [40] methyl 3-(thiophen-2-yl)propiolate (2 l), [41] methyl 3-(pyridin-2-yl)propiolate (2 k), [42] methyl (1-methoxycarbonylethynylcyclopropyl)propiolate (2 m), [43] cyclopropylacetylene (2 v), [44] CpCuPA C H T U N G T R E N N U N G (OMe) 3 , [19] 1-deuterohex-1-yne ([D]2 r) [45] were prepared according to literature procedures. Commercial nanosize-copper powder (Aldrich) was preactivated by heating in vacuo (0.05 mbar) at 150 8C overnight, and it was then stored under Ar.…”

Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme’s Surface-Exposed Front Region

“…PdCl2(PPh3)2/PPh3, argon, 2 M Na2CO3 or K-acetate, toluol or DMF, 120 or 80°C. 75 thioether 5d could be isolated in 12% yield by column chromatography. 42 As side products (SP), the related 2-aminothiazole derivative (SP1, m/z ) 305), an obvious S-oxidation artifact of 5d (SP2, m/z ) 335), and higher amounts of debrominated starting material (ethanone 1b) were identified (GC-MS) and separated.…”

Fe(II)-Catalyzed Amination of Aromatic C−H Bonds via Ring Opening of 2H-Azirines: Synthesis of 2,3-Disubstituted Indoles

“…Fe stands out among commonly used metals because it is far cheaper than Pd or Rh, abundant, and generally non-toxic. FeCl 2 has been reported to catalyze cleavage of azirines to form N-N bonds9a,b or open azirine rings as a stoichiometric one-electron donor 9c. To the best of our knowledge, the rearrangement of azirines to indoles is not known to be catalyzed by FeCl 2 .…”

“…Pyridines that are generally inert in electrophilic substitution reactions participated in the rearrangement. Other potential pathways such as opening the azirine ring via a radical pathway9c was ruled out based on formation of indole 2g with the cyclopropyl group intact. Submission of penta-deuterated substrate 1o to the optimized condition revealed a kinetic isotope effect of 1.3 (eq 1).…”