Palladium-Catalyzed Direct C7-Arylation of Substituted Indazoles

A novel direct C7-arylation of indazoles with iodoaryls is described using Pd­(OAc)₂ as catalyst, 1,10-phenanthroline as ligand, and K₂CO₃ as base in refluxing DMA. Direct C7-arylation of 3-substituted 1<i>H</i>-indazole containing an EWG on the arene ring gave the expected products in good isolated yields. In addition, a one-pot Suzuki–Miyaura/arylation procedure leading to C3,C7-diarylated indazoles has been developed

Palladium-Catalyzed Oxidative Direct C3- and C7-Alkenylations of Indazoles: Application to the Synthesis of Gamendazole

The first palladium-catalyzed oxidative alkenylation of (1<i>H</i>)- and (2<i>H</i>)-indazole derivatives with various olefins is described. The use of Pd­(OAc)₂ as the catalyst and Ag₂CO₃ as the oxidant promoted the selective C3-monoalkenylation of (1<i>H</i>)-indazoles and (2<i>H</i>)-indazoles, affording the desired products in good yields. An original oxidative C7-alkenylation of 3-substituted (1<i>H</i>)-indazoles was also developed. The oxidative alkenylation of (1<i>H</i>)-indazole was successfully applied to the total synthesis of the drug candidate gamendazole in a step- and atom-economical fashion

“On Water” Direct C‑3 Arylation of 2<i>H</i>‑Pyrazolo[3,4‑<i>b</i>]pyridines

An “on water” palladium-catalyzed direct (hetero)­arylation of 2<i>H</i>-pyrazolo­[3,4-<i>b</i>]­pyridines has been developed. The reactions proceeds smoothly with at low catalytic loading at low temperature providing the C3 (hetero)­arylated products in good to excellent isolated yields. Free <i>NH</i> 3-arylated 7-azaindazoles were also prepared by simple cleavage of the <i>N</i>-protected groups

Ligandless Palladium-Catalyzed Regioselective Direct C–H Arylation of Imidazo[1,2‑<i>a</i>]imidazole Derivatives

Herein a novel access to functionalizable 6-substituted imidazo­[1,2-<i>a</i>]­imidazole scaffolds is described. The reactivity of this heterobicyclic unit toward direct C–H arylation was studied, and conditions allowing regioselective arylation at position 3 were successfully developed. The practicability of this method is manifested by the ligandless conditions and low catalyst loading. The strategy is functional group tolerant and provides rapid access to a large variety of 3,6-di­(hetero)­arylated imidazo­[1,2-<i>a</i>]­imidazole derivatives. A second arylation at position 2 was then carried out, and a library of diversified 2,3,6-tri­(hetero)­arylated imidazo­[1,2-<i>a</i>]­imidazoles was generated in good yields. A one-pot, two-step procedure was finally developed

Ligandless Palladium-Catalyzed Regioselective Direct C–H Arylation of Imidazo[1,2‑<i>a</i>]imidazole Derivatives

Herein a novel access to functionalizable 6-substituted imidazo­[1,2-<i>a</i>]­imidazole scaffolds is described. The reactivity of this heterobicyclic unit toward direct C–H arylation was studied, and conditions allowing regioselective arylation at position 3 were successfully developed. The practicability of this method is manifested by the ligandless conditions and low catalyst loading. The strategy is functional group tolerant and provides rapid access to a large variety of 3,6-di­(hetero)­arylated imidazo­[1,2-<i>a</i>]­imidazole derivatives. A second arylation at position 2 was then carried out, and a library of diversified 2,3,6-tri­(hetero)­arylated imidazo­[1,2-<i>a</i>]­imidazoles was generated in good yields. A one-pot, two-step procedure was finally developed

Rational Design, Pharmacomodulation, and Synthesis of Dual 5‑Hydroxytryptamine 7 (5-HT₇)/5-Hydroxytryptamine 2A (5-HT_2A) Receptor Antagonists and Evaluation by [¹⁸F]-PET Imaging in a Primate Brain

We report the synthesis of 46 tertiary amine-bearing <i>N</i>-alkylated benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-ones, imidazo­[4,5-<i>b</i>]­pyridin-2­(3<i>H</i>)-ones, imidazo­[4,5-<i>c</i>]­pyridin-2­(3<i>H</i>)-ones, benzo­[<i>d</i>]­oxazol-2­(3<i>H</i>)-ones, oxazolo­[4,5-<i>b</i>]­pyridin-2­(3<i>H</i>)-ones and <i>N</i>,<i>N</i>′-dialkylated benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-ones. These compounds were evaluated against 5-HT₇R, 5-HT_2AR, 5-HT_1AR, and 5-HT₆R as potent dual 5-HT₇/5-HT_2A serotonin receptors ligands. A thorough study of the structure–activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)­piperidin-1-yl)­butyl)-1<i>H</i>-benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-one (<b>79</b>) and 1-(6-(4-(4-fluorobenzoyl)­piperidin-1-yl)­hexyl)-1<i>H</i>-benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-one (<b>81</b>) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, <i>K</i>_B = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, <i>K</i>_B = 0.6 and 16 nM, respectively) signaling pathways of 5-HT₇R and 5-HT_2AR. Both antagonists crossed the blood–brain barrier as evaluated with [¹⁸F] radiolabeled compounds <b>[</b>^<b>18</b><b>F]­79</b> and <b>[</b>^<b>18</b><b>F]­81</b> in a primate’s central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT₇R and 5-HT_2AR in the CNS

Design, Synthesis, and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/mTOR Dual Inhibitors

The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments