Pyrazole Scaffold Research Articles

Access to Bicyclo[3.1.0]hexane and Cyclopenta[c]pyrazole Scaffolds via Solvent-Directed Divergent Reactivity of 5-Iodotriazoles.

Divergent access to bicyclo[3.1.0]hexane and cyclopenta[c]pyrazole scaffolds bearing azole and azine units has been developed. The approach involves intramolecular cyclization of 5-iodo-1,2,3-triazoles acting as stable diazoimine precursors with concomitant noncatalytic (3 + 2)-cycloaddition. The choice of solvent allows control of the outcome of the cascade transformation. The developed procedure is simple and cost-efficient and allowed important heterocycles to be obtained in one-pot with various functional groups.

Novel Insecticidal Benzo[4,5]imidazo[1,2-b]pyrazole Derivatives Identified through Ring-Closure Scaffold Hopping on Fipronil.

A series of innovative benzo[4,5]imidazo[1,2-b]pyrazole scaffold containing compounds were rationally designed through a ring-closure scaffold hopping strategy and synthetized with an intermediate derivatization approach. Physicochemical properties analysis indicated the potential pesticide-likeness of the target compounds. The optimal target compound A14 showed relatively good insecticidal activity against P. xylostella, with an LC50 value of 37.58 mg/L, and demonstrated lower acute fish toxicity compared to fipronil. Docking binding mode analysis demonstrated that compound A14 bound to GABAR through a H-bond between the amide group and the residue of 6'Thr. The differences in binding modes between benzo[4,5]imidazo[1,2-b]pyrazole target compounds and fipronil may be a key factor for the reduced insecticidal activities. The elucidated binding mode and SAR profile lay a foundation for the further structural optimization of insecticidal benzo[4,5]imidazo[1,2-b]pyrazole derivatives.

Studi Molecular Docking dan Evaluasi Farmakokinetik Senyawa Analog Pirazol Turunan Benzen-Sulfonilurea sebagai Inhibitor Enzim Aldose Reduktase and α-Glukosidase Menggunakan Pendekatan In Silico

The pyrazole scaffold modification in various chemical structures on several studies has shown various biopharmacological activities. This study aims to predict the potential inhibition of pyrazole analogs derived benzene-sulfonylurea (4A, 4B, 4E, 5A, 5C, 5D) against the α-glucosidase (3A4A) and aldose reductase (3RX2) enzymes based on a molecular docking approach using Molecular Operating Environment (MOE) 2020.0102 software and evaluate pharmacokinetic profile (ADMET). In this study, the six test compounds were obtained from previous studies that have been proven antihyperglycemic. The results showed that all the 3,5-disubstituted benzene-sulfonylurea derivative pyrazole analogs are predicted to have low inhibitory activity against the α-glucosidase enzyme. Further, all compounds showed good aldose reductase inhibitor activity and had lower binding free energy values ​​than tolrestat as the positive control (-6.82 kcal/mol). Compound 5C has the best potential inhibitory activity against the aldose reductase enzyme compared to the other test compounds, because it has the lowest binding free energy value (-8.76 kcal/mol) and interacts with important residues on the receptor forming four hydrogen bonds, namely the carbonyl group of SO2 with residues Trp111 and His110, and the carbonyl group of the amide with residues His110 and Tyr48, as well as 3 hydrophobic bonds, namely a pyrazole ring with residues Leu300, Trp219 and a furan ring with Phe122. ADMET properties of the compounds are also predicted. This information provides an opportunity for a 5C compound as an aldose reductase inhibitor agent to develop drug candidates with better and safer activities.

Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold

The calcium release activated calcium (CRAC) channel is highly expressed in T lymphocytes and plays a critical role in regulating T cell proliferation and functions including activation of the transcription factor nuclear factor of activated T cells (NFAT), cytokine production and cytotoxicity. The CRAC channel consists of the Orai pore subunit and STIM (stromal interacting molecule) endoplasmic reticulum calcium sensor. Loss of CRAC channel mediated calcium signaling has been identified as an underlying cause of severe combined immunodeficiency (SCID), leading to drastically weakened immunity against infections. Gain-of-function mutations in Orai and STIM have been associated with tubular aggregated myopathy (TAM), a skeletal muscle disease. While a number of small molecules have shown activity in inhibiting the CRAC signaling pathway, the usefulness of those tool compounds is limited by their off-target activity against TRPM4 and TRPM7 ion channels, high lipophilicity, and a lack of understanding of their mechanism of action. We report structure-activity relationship (SAR) studies that resulted in the characterization of compound 4k [1-(cyclopropylmethyl)-N-(3-fluoropyridin-4-yl)-1H-indazole-3-carboxamie] as a fast onset, reversible, and selective CRAC channel blocker. 4k fully blocked the CRAC current (IC50: 4.9 μM) and the nuclear translocation of NFAT at 30 and 10 μM, respectively, without affecting the electrophysiological function of TRPM4 and TRPM7 channels. Computational modeling appears to support its direction binding to Orai proteins that form the transmembrane CRACchannel.

Discovery of novel thiazole derivatives containing pyrazole scaffold as PPAR-γ Agonists, α-Glucosidase, α-Amylase and COX-2 inhibitors; Design, synthesis and in silico study

A novel series of thiazole derivatives with pyrazole scaffold 16a-l as hybrid rosiglitazone/celecoxib analogs was designed, synthesized and tested for its PPAR-γ activation, α-glucosidase, α-amylase and COX-2 inhibitory activities. Regarding the anti-diabetic activity, all compounds were assessed in vitro against PPAR-γ activation, α-glucosidase and α-amylase inhibition in addition to in vivo hypoglycemic activity (one day and 15 days studies). Compounds 16b, 16c, 16e and 16 k showed good PPAR-γ activation (activation % ≈ 72–79 %) compared to that of the reference drug rosiglitazone (74 %). In addition, the same derivatives 16b, 16c, 16e and 16 k showed the highest inhibitory activities against α-glucosidase (IC50 = 0.158, 0.314, 0.305, 0.128 μM, respectively) and against α-amylase (IC50 = 32.46, 23.21, 7.74, 35.85 μM, respectively) compared to the reference drug acarbose (IC50 = 0.161 and 31.46 μM for α-glucosidase and α-amylase, respectively). The most active derivatives 16b, 16c, 16e and 16 k also revealed good in vivo hypoglycemic effect comparable to that of rosiglitazone. In addition, compounds 16b and 16c had the best COX-2 selectivity index (S.I. = 18.7, 31.7, respectively) compared to celecoxib (S.I. = 10.3). In vivo anti-inflammatory activity of the target derivatives 16b, 16c, 16e and 16 k supported the results of in vitro screening as the derivatives 16b and 16c (ED50 = 8.2 and 24 mg/kg, respectively) were more potent than celecoxib (ED50 = 30 mg/kg). In silico docking, ADME, toxicity, and molecular dynamic studies were carried out to explain the interactions of the most active anti-diabetic and anti-inflammatory compounds 16b, 16c, 16e and 16 k with the target enzymes in addition to their physiochemical parameters.

Design, Antimicrobial Testing, and Molecular Docking Studies of New Chalcone and Pyrimidine Derivatives based on 2-phenyl-1H-pyrazol-3(2H)-one

Background & Objectives: Heterocyclic pyrimidine and pyrazole rings have attracted the interest of medicinal chemists because of their pharmacological potential including antimicrobial activity. Based on molecular hybridization, new chalcones 6a-g and pyrimidines 7a-g based on a pyrazole scaffold were designed. Methods: The synthesis of these compounds involved mild condensation reactions between compound 4 and various aromatic aldehydes in a mixture of ethanol/NaOH (95:5 v/v) to give the corresponding chalcones 6a-g. These chalcones were further reacted with urea in the presence of a base in ethanol to produce the pyrimidine derivatives 7a-g. These new candidates were screened for their in vitro antimicrobial activities and molecular docking studies were evaluated. Results: The antibacterial and antifungal studies of all synthesized compounds against the strains tested showed that compounds 6c, d, and 7c, d exhibited the highest antibacterial and antifungal activities. In addition, the structure-activity relationship and docking studies are discussed. Conclusion: The synthesized compounds 6c, 6d, 7c, and 7d showed the highest antibacterial and antifungal activities against the tested strains.

Magnetic Nanoparticles‐Supported Synthesis of Pyrazole Scaffolds: A Review

AbstractIn the present era, the concept of green in organic synthesis has a unique and irreplaceable place. Specifically, nanoparticle has gained much more attention due to its various properties related to the concept of green chemistry. In this context, magnetic nanoparticle has been widely used in the organic synthesis over last one decade. Among organic compounds, pyrazole and its scaffolds are recognized as a privileged structure as it represents a promising area for identification of lead structures towards the discovery of new synthetic drug molecules and other valuable candidates. Several commercial drugs such as Sildenafil, Rimonabant, Celecoxib and many other compounds in biological testing and preclinical evaluation, illustrate the wide therapeutic spectrum in this class of drug scaffolds. Accordingly, the magnetic nanoparticles have an irreplaceable place in the synthesis of pyrazole derivatives and it is a green and easy methodology to the organic chemists. The present manuscript represents the assimilation of literature pertaining to green aspects of magnetic nanoparticles for the synthesis of highly diversified and valuable derivatives of pyrazole.

1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) as a reusable promoting medium for the catalyst-free and green synthesis of dihydropyrano[2,3-c]pyrazole scaffolds

A manufactured protocol that is both helpful and free of catalyst has been presented for the production of dihydropyrano[2,3-c]pyrazole frameworks in polyfluorinated alcohol as a reusable promoting medium. All reactions are completed quickly, and the products are obtained in astounding yields. Notably, the convenient approach has remarkable yields, avoids the use of hazardous solvents or reagents, is simple to operate, and only requires one pot. The 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was extremely stable and could be repeated four times without significant basic alteration or action, making it ideal for large-scale and organic production.

Investigations of Antioxidant and Anti-Cancer Activities of 5-Aminopyrazole Derivatives.

To further extend the structure-activity relationships (SARs) of 5-aminopyrazoles (5APs) and identify novel compounds able to interfere with inflammation, oxidative stress, and tumorigenesis, 5APs 1-4 have been designed and prepared. Some chemical modifications have been inserted on cathecol function or in aminopyrazole central core; in detail: (i) smaller, bigger, and more lipophilic substituents were introduced in meta and para positions of catechol portion (5APs 1); (ii) a methyl group was inserted on C3 of the pyrazole scaffold (5APs 2); (iii) a more flexible alkyl chain was inserted on N1 position (5APs 3); (iv) the acylhydrazonic linker was moved from position 4 to position 3 of the pyrazole scaffold (5APs 4). All new derivatives 1-4 have been tested for radical scavenging (DPPH assay), anti-aggregating/antioxidant (in human platelets) and cell growth inhibitory activity (MTT assay) properties. In addition, in silico pharmacokinetics, drug-likeness properties, and toxicity have been calculated. 5APs 1 emerged to be promising anti-proliferative agents, able to suppress the growth of specific cancer cell lines. Furthermore, derivatives 3 remarkably inhibited ROS production in platelets and 5APs 4 showed interesting in vitro radical scavenging properties. Overall, the collected results further confirm the pharmaceutical potentials of this class of compounds and support future studies for the development of novel anti-proliferative and antioxidant agents.

Synthesis and Characterization of Novel Heteroarylacrylonitrile Derivatives Containing Pyrazole Scaffold

2,3-disubstituted acrylonitriles derivatives are among the most important molecules in medicinal chemistry due to their bioactivity and their role as starting compounds for many bioactive molecules. Many heterocyclic structures have been investigated as AChE enzyme inhibitors. Nowadays, E/Z acrylonitrile derivatives are being studied as new AChE inhibitors. This study aimed to synthesis new heteroaryl-acrylonitrile compounds using Knoevenagel condensation. In this context, acrylonitrile compounds with aryl and heteroaryl structures at positions 2 and 3 (respectively )were synthesized from the reactions of pyrazole aldehyde derivative (4) with various acetonitrile compounds. Synthesized novel heteroarylacrylonitrile derivatives (5a-d) containing pyrazole ring are potential AChE inhibitors. The structures of the synthesized compounds were elucidated by FTIR, 1H-NMR and 13C-NMR spectroscopic techniques.

Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

Pyrazole Scaffolds Having Promising Pharmacological Potential: A Review.

Heterocyclic compounds have diverse structure, which makes them broad and economical therapeutic agents. Pyrazole is a five-membered aromatic ring that contains two nitrogen atom and is responsible for the diverse functions of heterocyclic compounds. This implies the need of reviewing the work that already has been done on the potential of pyrazole scaffolds in the field of medicinal chemistry for the synthesis of new compounds with more effective antimicrobial, antioxidant, anticancer, anti-tuberculosis, and anti-inflammatory activities.

Pyrimidine Tethered Pyrazoles: Synthesis, Biological, and Molecular Docking Studies

A series of pyrimidine integrated pyrazoles (5a?5g) has been synthesized in good yields from aryl hydrazines and aralkyl ketones through a protocol of multi-steps such as condensation/imine formation, cyclization/Vilsmeier-Haackreaction, and Knoevenagelcondensation and characterized through physical and spectral techniques. 2,2-diphenylpicrylhydrazyl radical scavenging evaluation revealed that the chemical entity possessing para-fluoro substituent on the aromatic unit tethered at the carbon of pyrazole scaffold 5g exerted the highest activity among the investigated ones. Of the results of cytotoxicity evaluation utilizing AsPC1, BxPC3, SW1990 (pancreatic cancer cells), the chemical entity possessing ortho-chlorosubstitient on the aryl unit integrated at carbon of pyrazole scaffold 5b exhibited superior activity. Besides, the molecular docking studies of the ortho-chloroaryl group possessing chemical entity 5b with BCL-2 (B-cell lymphoma 2) displayed significant binding affinity (-9.1 kcal mol-1). In addition, pharmacokinetic as well as prediction of drug-likeness for all the molecular hybrids 5a?5g have been evaluated using SwissADME tool and all the chemical entities are in good agreement of Lipinski rule with no violation.. KEYWORDS :Cytotoxicity, Molecular docking, Pyrazoles, Pyrimidines, Radical scavenging, SwissADME.

In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic.

In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base-pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer's (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer's (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.

A novel alpha-amylase inhibitor-based spirooxindole-pyrrolidine-clubbed thiochromene-pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory.

A novel spirooxindole-pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene-based thiochromene and pyrazole scaffolds with the secondary amino-acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS-on is 13.9 kcal mol-1 below the separated reagent. This 32CA, which takes place through a non-concerted one-step mechanism, presents a total ortho regio- and endo stereoselectivity, which is controlled by the formation of two intramolecular H… O hydrogen bonds. The design of spirooxindole-pyrrolidines engrafted thiochromene and pyrazole was tested for alpha-amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole-pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).

Carbazole-based photocatalyst (4CzIPN) as a novel donor-acceptor fluorophore-catalyzed visible-light-induced photosynthesis of dihydropyrano[2,3-c]pyrazole scaffolds via a proton-coupled electron transfer process

Carbazole-based photocatalyst (4CzIPN) as a novel donor-acceptor fluorophore-catalyzed visible-light-induced photosynthesis of dihydropyrano[2,3-c]pyrazole scaffolds via a proton-coupled electron transfer process

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies.

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.

Recent Advances in the Microwave and Ultrasound-Assisted Synthesis of Pyrazole Scaffolds

Abstract: Pyrazoles are well-known five-membered heterocyclic compounds and are found in a wide variety of synthetic and natural compounds. Compounds carrying pyrazole scaffolds exhibit a wide range of biological activities such as anticancer, antimicrobial, anticonvulsant, antioxidant, analgesic and anti-inflammatory effects. Pharmaceuticals with many different activities in the pyrazole structure are currently on the market (e.g., celecoxib, lonazolac, tepoxalin, rimonabant, pyrazofurin, epirizole). The pyrazole ring contains the N-N double bond, which is thought to have a key role in biological activity, and compounds with this bond are difficult to produce by organisms, so their relative abundance is very low in nature. For this reason, many studies have been carried out on this structure and it has been revealed that the structure has a unique effect spectrum. Microwave-assisted synthesis has opened up some new opportunities compared to conventional synthesis. It is possible to use less solvent and reduce processing time with microwave synthesis. In addition, better selectivity and thermal stability are provided by microwave synthesis. Ultrasound-assisted synthesis is often used to enhance conventional solvent extraction, while microwaves reveal bioactive compounds by heating without any solvent. In the traditional method of pyrazole synthesis; polar solvents, acidic and basic catalysts are needed in large quantities in the synthesis of pyrazole scaffolds. This review aims to summarize the recent advancements in the synthesis methods of a pyrazole ring with non-traditional methods. Therefore this article will provide readers with a new perspective on the synthesis of pyrazole scaffolds as an environmentally friendly alternative.

Discovery a novel of thiazolo[3,2-a]pyridine and pyrazolo[3,4-d]thiazole derivatives as DNA gyrase inhibitors; design, synthesis, antimicrobial activity, and some in-silico ADMET with molecular docking study

In our continuous efforts to develop novel and effectual antimicrobial agents, we herein synthesized a novel thiazolo[3,2-a]pyridine and pyrazolo[3,4-d]thiazole derivatives hybrid with pyrazole scaffold. The structure of seventeen synthesized derivatives was confirmed using IR, NMR, Mass spectra, and elemental analysis. The desired compounds have undergone an appraisal for their antimicrobial activity in vitro against six clinical MDR bacterial and fungal isolates through the agar well-diffusion, demonstrating promising results. Additionally, five thiazolo[3,2-a]pyridine derivatives 2a, 2e, 2g, 3c, and 3d revealed significant potent activity against the tested pathogens, with compound 2e as the most active compound with values ranging MIC = 0.125–0.25 µg/mL and MBC = 0.0625–0.125 µg/mL against bacterial isolate and MIC = 0.25 µg/mL and MFC = 0.125 µg/mL against two fungal isolates. In the MBC, MFC, and time-kill, the active target compounds showed -cidal activities towards the pathogenic isolates at different concentrations, and the isolates were not recovered from the treated groups with 1XMIC after 6-24 h of bacterial incubation and after 12 h of fungal incubation, confirming -cidal activity. Moreover, compound 2e exhibited DNA gyrase inhibitor with IC50 = 7.35 µM compared with Ciprofloxacin (IC50 = 47.68 µM). Finally, the docking simulation was performed to determine the mode of molecular interaction. The results exhibited that compound 2e revealed the lowest binding energy S = - 20.84 Kcal/mol compared with Ciprofloxacin S = -13.67 Kcal/mol. In silico, ADMET displayed that compound 2e obeys the Lipinski rule and, therefore, is predicted to be oral bioavailability with a non-toxic and skin sensitization profile.

Development of Versatile Routes for the Preparation of an Intermediate to Immuno-Oncology Agonist BMS-986299

The development and optimization of two efficient and convenient routes for the construction of synthetic equivalents of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline, a key intermediate to immuno-oncology agonist (BMS-986299), is described. The developed routes started from commercial available reagents into the desired pyrazole scaffolds smoothly with different substituents such as THP-, Bn-, and PMB-group tolerance. Finally, to further demonstrate the practicability, a large-scale process (10–30 g on a laboratory scale) was obtained through a simple crystallization or filtration without any column chromatography needed and may be suitable for the scalable production of the key intermediate for industrial applications.