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Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC50 =0.16 μM, EC50 =0.3 μM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

The synthesis of functionalized pyrazolo[1,5-a]pyridines through oxidative [3+2] cycloaddition of N-aminopyridines with α,β-unsaturated carbonyl compounds or electron-withdrawing olefins is described. The reactions proceed in N-methylpyrrolidone as the solvent under metal-free conditions at room temperature.

Copper–mediated synthesis of various pyrazolo[1, 5–a]pyridine-3-carboxylates has been described. The biological activities of these molecules have been evaluated against various human cancer cell lines A549 (Lung adenocarcinoma cell line), MCF-7 (Breast carcinoma cell line), HCT-116 (Colon cancer cell line), and PC-3 (Prostate cancer cell line) through SRB assay. Compound 247 led to accumulation MCF-7 cells in G1-phase and revealed its important role in mitotic cell cycle progression.

The synthesis of imidazo[1,5-a]pyridines through denitrogenative transannulation of pyridotriazoles with nitriles using BF3·Et2O as catalyst has been described. The combination of solvents (dichlorobenzene-dichloroethane) plays a crucial role in achieving quantitative yields of desired products under metal-free conditions.

N-Acylation of anilines with 1, 3-diketones promoted by AIBN (2-2′-azoisobutyronitrile) under metal-free and peroxide-free conditions in the presence of molecular oxygen as oxidant has been described. This protocol proceeds by the oxidative cleavage of C–C bond with simultaneous intermolecular C–N bond formation under mild conditions.

Iodine catalyzed synthesis of indolizine-1-carboxylates through oxidative C C and C N bond formations by the reaction of 2-pyridyl acetates with alkynes and alkenes without metal, oxidant, and base. This procedure is compatible with a broad range of functional groups in both alkynes and alkenes with good yields. The reaction proceeds through a tandem C C bond formation followed by an intramolecular cyclization.

The copper-catalyzed aerobic oxidative synthesis of imidazo[1,5-a]pyridines via cascade denitrogenative transannulation reaction of pyridotriazoles with benzylamines with good functional group tolerance is developed. The present methodology is also applicable to amino acids to obtain imidazo[1,5-a]pyridines via decarboxylative oxidative cyclization.

Copper-catalyzed regioselective C-3 sulfenylation of imidazo[1,2-a]pyridines using p-tosylchloride as a benign source of sulfenylating agents has been developed. On the other hand, p-tosylchloride mediated thiomethylation of imidazo[1,2-a]pyridines with dimethylsulfoxide as a source of thiomethylation under metal-free conditions was also described.

Synthesis of indolizine-1-carboxylates through the Ortoleva-King reaction of 2-pyridylacetate followed by the Aldol condensation under mild reaction conditions has been described. This protocol is compatible with a broad range of functional groups, and it has been also successfully extended to unsaturated ketones, bringing about the regioselective formation of benzoyl-substituted indolizines through Michael addition followed by C-N bond formation, which are difficult to prepare by previous methods in a single step.

Copper-mediated synthesis of pyrazolo[1,5-a]pyridine-3-carboxylates through oxidative linkage of C-C and N-N bonds under mild reaction conditions is described. This protocol is applicable to a variety of pyridyl esters as well as various benzonitriles including nicotinonitrile, isonicotinonitrile and thiophene-2-carbonitrile. Better yields were observed with electron withdrawing substituted benzonitriles.

Efficient transamidation of unactivated carboxamides, phthalimides, formamides and thioamides with amines under solvent-free conditions using H-β-zeolite as a green and recyclable heterogeneous catalyst is described. Easy work up, high purity of the products, recyclability and environmentally-friendly nature of the catalyst are the attractive features of the present methodology. This is the first report for the transamidation of thioamides under heterogeneous conditions.

Synthesis of 2 or 3-(hetero)aryl pyrazolo[1,5-a]pyridines through [3 + 2] cycloaddition ofN-aminopyridine with β-nitrostyrenes followed byin situdenitration under metal-free and mild conditions are described.

Copper-catalyzed synthesis of imidazo[1,5-a]pyridine-1-carboxylates through oxidative amination of C(sp(3))-H bonds under mild aerobic conditions with broad substrate scope is described. Use of naturally abundant air as the sole oxidant was found to be efficient and selective. The present protocol is also applicable for direct synthesis of functionalized imidazo[1,5-a]pyridines from amino acid derivatives.

A metal- and peroxide-free N-acylation of anilines with 1,3-diketones with oxygen as oxidant yields the corresponding N-aryl amides under mild conditions.

Metal-free synthesis of substituted imidazole [1,2-a]pyridines from deprotective N-(prop-2-yn-1-yl)pyridin-2-amines in water is elucidated. Electron releasing substituents on pyridine ring provided pure products in quantitative yields without separation by column chromatography.

Received: May 20, 2013; Published online: August 9, 2013Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300456.Abstract: We report here an operationally simplecopper-catalysed synthesis of imidazoACHTUNGRE[1,2- a]pyri-dines through C H activation with oxidative link-age of two C N bonds under very mild conditionsusing molecular oxygen as a sole oxidant. The pro-cess allows the quick assembly of imidazoACHTUNGRE[1,2- a]pyr-idines including the antiulcer drug zolimidine frominexpensive and readily available 2-aminopyridinesand methyl ketones with broad range of functionalgroup tolerance.Keywords: aerobic oxidation; C H activation;copper; imidazoACHTUNGRE[1,2- a]pyridines; zolimidine synthe-sisThe transition metal-catalysed direct C N bond for-mation through C H activation by the formal loss ofH

In the presence of a catalytic amount of L-proline (10 mol %), transamidations of carboxamides with amines were achieved under solvent-free conditions. The transamidation process is compatible with a wide range of amines.

Aqueous syntheses of methylimidazo[1,2-a]pyridines without any deliberate addition of catalyst are reported. Imidazo[1,2-a]pyrazine and imidazo[2,1-a]isoquinoline were also obtained in good yields under similar conditions. With acetonitrile as solvent, Ag-catalyzed intramolecular aminooxygenation produced imidazo[1,2-a]pyridine-3-carbaldehydes in moderate to good yields.

The copper-catalyzed aerobic oxidative synthesis of imidazo[1,5-a]pyridines via cascade denitrogenative transannulation reaction of pyridotriazoles with benzylamines with good functional group tolerance is developed. The present methodology is also applicable to amino acids to obtain imidazo[1,5-a]pyridines via decarboxylative oxidative cyclization.

Copper-catalyzed regioselective C-3 sulfenylation of imidazo[1,2-a]pyridines using p-tosylchloride as a benign source of sulfenylating agents has been developed. On the other hand, p-tosylchloride mediated thiomethylation of imidazo[1,2-a]pyridines with dimethylsulfoxide as a source of thiomethylation under metal-free conditions was also described.

A green method for the transamidation and thioamidation using H-β-zeolite as heterogeneous recyclable catalyst is developed.

The hydroarylation of styrenes with various arene(heteroarene) compounds using H-β-zeolite as a green and recyclable heterogeneous catalyst under mild reaction conditions has been developed. The catalyst showed versatility and high selectivity (up to 100 %) of desired 1,1-diarylalkanes in cyclohexane as solvent under the conditions studied. The catalyst could be reactivated by simple treatment with mineral acid at room temperature for better catalytic activity.

An Ortoleva—King reaction of pyridineacetate and ketones followed by intramolecular Aldol condensation under mild reaction conditions affords indolizine-1-carboxylates.

Synthesis of (hetero)aryl pyrazolo[1,5-a]pyridines through [3 + 2] cycloaddition of N-aminopyridine with β-nitrostyrenes followed by in situ denitration and oxidation under metal-free, mild conditions are described.

Copper-catalyzed synthesis of imidazo[1,5-a]pyridine-1-carboxylates through oxidative amination of C(sp3)—H bonds is described.

Pyrazolopyridinecarboxylates are furnished under mild conditions from commercially available pyridyl ester and benzonitriles.

A series of amide derivatives (I) and (IV) as well as more challenging aryl and alkyl amines (VII) with long-chain alkyl substituents are selectively converted into the corresponding transamidation products (III), (VI) and (IX), which are frequently found in biologically active compounds.

The novel protocol allows the regioselective sulfenylation of a wide variety of imidazoheterocycles under mild and metal-free reaction conditions.

The reaction conditions are unsuitable for the transformation of aminothiazoles, pyrimidines and pyrazines.

Regioselective sulfenylation of imidazoheterocycles with thiophenols at room temperature is reported. Sulfenylation is promoted by N-chlorosuccinimide under metal-free conditions with a broad range of substrate scopes.

A simple metal-free protocol is developed for the title hydroamination reaction which is also successfully applied to the synthesis of imidazopyrazine derivative (IV).

The reaction proceeds through C—H activation with oxidative linkage of two C—N bonds under mild conditions and oxygen as a sole oxidant.

This novel method provides an access to a wide range of different substituted aminoheterocycles under mild conditions by using catalytic amounts of NaOH or equimolar amounts in case of the synthesis of compounds (VII) and (IX).

The transamidation of carboxamides is achieved under solvent-free conditions providing a wide range of aliphatic, propargylic, benzylic, aromatic, and heteroaromatic transamidation products in moderate to high yields.

In the presence of a catalytic amount of NaOH, the selective N-alkylation of various heteroaromatic primary amines is reported. With 1 equiv of NaOH, N1,C5-dialkylation of 4-phenyl-2-aminothiazoles has been investigated. Reaction of in situ generated aldehyde with amine yields the N-alkylated and N1,C5-dialkylated products through hydride ion transformation from alcohol.

Aqueous syntheses of methylimidazo[1,2-a]pyridines without any deliberate addition of catalyst are reported. Imidazo[1,2-a]pyrazine and imidazo[2,1-a]isoquinoline were also obtained in good yields under similar conditions. With acetonitrile as solvent, Ag-catalyzed intramolecular aminooxygenation produced imidazo[1,2-a]pyridine-3-carbaldehydes in moderate to good yields.