Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

Regioselective Synthesis of C3-Hydroxyarylated Pyrazoles.

Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not require the C4 and C5 positions of the pyrazole to be functionalized to observe regioselectivity. Using this method, we completed the synthesis of a recently reported JAK 1/2 inhibitor. Our synthesis produces the desired product in 4 steps from commercially available starting materials.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.

Possible competitive modes of decarboxylation in the annulation reactions of ortho-substituted anilines and arylglyoxylates.

Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of K2S2O8 at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of K2S2O8 and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-rich ortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of K2S2O8, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent K2S2O8, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.

Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D. Optimization of our hit compound 1a (IC50 = 29 nM) led to the highly potent mono sulphonamide analogue 4b (IC50 = 4 nM), however with poor microsomal stability (HLM: 177 and MLM: 177 µl/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structure-activity relationship screen which led to the identification of our optimised lead 24e (IC50 = 45 nM), with an improved microsomal stability (HLM: 59.1 and MLM: 86.8 µl/min/mg). Our efforts reveal that 24e could be a good starting point or potential candidate for further preclinical studies against diseases where Cathepsin D plays an important role.

Intramolecular Acylation of Unactivated Pyridines or Arenes via Multiple C-H Functionalizations: Synthesis of All Four Azafluorenones and Fluorenones.

An unprecedented intramolecular acylation of unactivated pyridines via multiple C(sp3/sp2)-H functionalizations of a methyl, hydroxymethyl, or aldehyde group has been developed providing a general access to all four azafluorenones. The application of this protocol is further demonstrated to the synthesis of azafluorenone related fused nitrogen heterocycles and fluorenones. In addition, design and synthesis of a novel fluorene based organic emitter for potential use in organic light emitting devices (OLEDs) is also reported.

Intramolecular Minisci acylation under silver-free neutral conditions for the synthesis of azafluorenones and fluorenones.

Despite its synthetic potential, intramolecular acylation by the Minisci reaction remains unexplored. The development of a new intramolecular Minisci acylation under silver-free neutral conditions providing access to azafluorenones and fluorenones is described. Distinct from the current literature known approaches for Minisci acylation, the report described herein features a method that: (a) avoids the use of silver that is invariably used in Minisci acylation, (b) does not require any acidic conditions for the activation of pyridines, and

Palladium-Catalyzed Serendipitous Synthesis of Arylglyoxylic Amides from Arylglyoxylates and N,N-Dialkylamides in the Presence of Halopyridines.

A palladium-catalyzed synthesis of arylglyoxylic amides by the reaction of arylglyoxylates and N,N-dialkylamides in the presence of a 2,3-dihalopyridine has been realized for the first time. An anticipated 2,3-diaroylpyridine did not form in this reaction. The current study unveils an unprecedented role of 2,3-dihalopyridine toward this amidation. Our mechanistic study reveals that the arylglyoxylate could react with halopyridine to form a traceless activated pyridyl ester of arylglyoxylic acid, which upon subsequent reaction with amino surrogate, N,N-dialkylamides could form the arylglyoxylic amides.

Palladium-Catalyzed Decarboxylative Ortho-Acylation of Tertiary Benzamides with Arylglyoxylic Acids.

A palladium-catalyzed ortho-acylation of tertiary benzamides using arylglyoxylic acids has been described. Unlike the palladium insertion reported to occur in the distorted N-C(O) amide bond of tertiary benzamides, the current study unveils ortho C-H palladation in acylic or cyclic N,N-dialkylbenzamides affording ortho-acylated tertiary benzamides in good to excellent yields. Our experimental study on the mechanism provides information on the tendency of the amide nitrogen toward weak coordination with palladium as opposed to oxygen. However, density functional theory calculations suggest coordination of amide oxygen to palladium, which makes the mechanism especially interesting. A Pd(II)/Pd(III) catalytic cycle and nucleophilic attack by the acyl radical rather than arylglyoxylate anion are supported by mechanistic studies.

Formation of amides, their intramolecular reactions for the synthesis of N-heterocycles, and preparation of a marketed drug, sildenafil: a comprehensive coverage.

A unified approach to the tandem preparation of diverse nitrogen heterocycles via decarboxylative acylation of ortho-substituted amines with α-oxocarboxylic acids and subsequent intramolecular cyclizations has been developed. The key features of this work include: the first example of transition-metal-free decarboxylative amidation of α-oxocarboxylic acids with ortho-substituted amines, realization of intramolecular cyclization of amides employing nucleophiles that have previously been unexplored, mechanistic investigation of an unprecedented K2S2O8 promoted amide formation and its subsequent intramolecular cyclizations, and application to the synthesis of a best-selling marketed drug.

Metachronous bilateral segmental testicular infarction: multi-parametric ultrasound imaging with grey-scale ultrasound, Doppler ultrasound, contrast-enhanced ultrasound (CEUS) and real-time tissue elastography (RTE).

Segmental testicular infarction is a rare cause of acute scrotal pain. The appearances on grey-scale sonography are often indistinguishable from that of a testicular tumour, resulting in unnecessary orchiectomy. We report a case of acute bilateral testicular infarction, of unknown etiology, which was conservatively managed to resolution following a confident diagnosis achieved with the aid of contrast-enhanced ultrasound (CEUS) and real-time tissue elastography (RTE) along with conventional grey-scale and Doppler sonography. The evolving appearances on each of the sonographic modalities are described. We discuss the importance of complementing conventional sonography with CEUS and RTE in order to make a confident diagnosis and avoid unnecessary surgical intervention.