4695-57-2

Upstream product

• 79-37-8 oxalyl dichloride 
• 3424-93-9 4-methoxyphenylacetamide 
• 100-07-2 4-methoxy-benzoyl chloride 
• 3315-16-0 silver cyanate 
• 104825-42-5 1,1-Bis-(4-methoxy-benzoyl)-3,3-dimethyl-urea 

Downstream Products

• 14560-52-2 3-benzyl-6-(4-methoxy-phenyl)-2-phenyl-2,3-dihydro-[1,3,5]oxadiazin-4-one 
• 18354-39-7 4-methoxy-N-(phenylcarbamoyl)benzamide 
• 13187-57-0 4-(4-methoxy-benzoyl)-2,3-diphenyl-[1,2,4]oxadiazolidin-5-one 
• 19619-81-9 N-(4-Methoxybenzoyl)-peroxycarbamidsaeure-tert.-butylester 
• 36743-88-1 3-cyclohexyl-6-(4-methoxy-phenyl)-2-phenylimino-2,3-dihydro-[1,3,5]oxadiazin-4-one 
• 36743-78-9 3-cyclohexyl-2-cyclohexylimino-6-(4-methoxy-phenyl)-2,3-dihydro-[1,3,5]oxadiazin-4-one 
• 37586-17-7 6-(4-methoxy-phenyl)-4-phenylimino-3-o-tolyl-3,4-dihydro-[1,3,5]oxadiazin-2-one 
• 18354-43-3 2-(p-Methoxy-phenyl)-5-acetyl-5-methyl-1,3-oxazolin-4-on 
• 21631-70-9 5-benzoyl-2-(4-methoxy-phenyl)-oxazol-4-one 
• 132981-14-7 1-(4-Methoxy-benzoyl)-3-[3-(2,3,5,6-tetrahydro-imidazo[2,1-b]thiazol-6-yl)-phenyl]-urea 
• 130267-06-0 2-p-methoxyphenyl-4-acetoxy-6H-1,3-oxazin-6-one 
• 111860-87-8 2-p-methoxyphenyl-4-hydroxy-6H-1,3-oxazin-6-one 
• 73723-09-8 5-Dimethoxyphosphoryl-2-(4-methoxyphenyl)-1,3-oxazolin-4-on 
• 73723-11-2 5-Diphenylphosphoryl-2-(4-methoxyphenyl)-1,3-oxazolin-4-on 

Relevant academic research and scientific papers

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System**

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic in vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This in vivo assay substantiated the in vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.

Scalable Synthetic Strategy for Unsymmetrical Trisubstituted s-Triazines

A scalable synthetic strategy to produce a large variety of unsymmetrical trisubstituted 1,3,5-triazines was developed. This protocol applied in situ formed acyl isocyanate from amide to react with amidine, introducing two substituents to the 1,3,5-triazinone ring with a low production cost and a simple workup procedure. The scalability of this method was demonstrated by translating a small-scale procedure to a multi-kilogram-scale synthesis. Chlorination and a further coupling reaction with various nucleophiles could provide unsymmetrical trisubstituted 1,3,5-triazines bearing diverse functional groups.

Design, Synthesis, and Insecticidal Activity of Novel Doramectin Derivatives Containing Acylurea and Acylthiourea Based on Hydrogen Bonding

Our recent investigation on the insecticidal activities of several doramectin derivatives preliminarily revealed that the presence of hydrogen bonds at the C4″ position of the molecule with target protein γ-aminobutyric acid (GABA) receptor was crucial for retaining high insecticidal activity. As a continuation of our research work on the development of new insecticides, two series of novel acylurea and acylthiourea doramectin derivatives were designed and synthesized. The bioassay results indicated that the newly synthesized compounds (5o, 5t, and 6t) exhibited higher insecticidal activity against diamondback moth, oriental armyworm, and corn borer than the control compounds doramectin, commercial avermectins, chlorbenzuron, and lead compound 3g in our laboratory. Specifically, compound 5t was identified as the most promising insecticide against diamondback moth, with a final mortality rate of 80.00% at the low concentration of 12.50 mg/L, showing approximately 7.75-fold higher potency than the parent doramectin (LC50 value of 48.1547 mg/L), 6.52-fold higher potency than commercial avermectins (LC50 value of 40.5507 mg/L), and 3.98-fold higher potency than compound 3g (LC50 value of 24.7742 mg/L). Additionally, molecular docking simulations revealed that compound 5t (2.17, 2.20, 2.56, and 2.83 ?) displayed stronger hydrogen-bond action in binding with the GABA receptor, better than that of compound 5o (1.64 and 2.15 ?) and compound 6t (2.20 and 2.31 ?) at the C4″ position. This work demonstrated that these compounds containing hydrogen-bond groups might contribute to the improvement of insecticidal activity and supply certain hints toward structure optimization design for the development of new insecticides.

Aroyl Isocyanates as 1,4-Dipoles in a Formal [4 + 1]-Cycloaddition Approach toward Oxazolone Construction

A formal phosphine-mediated [4 + 1]-cycloaddition between a 1,2-dicarbonyl and an aroyl isocyanate to provide oxazolones bearing a disubstituted C5 center is described. By exploiting the carbene-like reactivity of oxyphosphonium enolates as C1 synthons and aroyl isocyanates as formal 1,4-dipoles, oxazolones and spiroooxindole oxazolones are constructed in high yields (39-99%).

Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase

Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.

Convenient One-Pot Two-Step Synthesis of Symmetrical and Unsymmetrical Diacyl Ureas, Acyl Urea/Carbamate/Thiocarbamate Derivatives, and Related Compounds

A wide range of chemicals such as amides, hydrazides, amines, alcohols, carbazate, and sulfonate were reacted with acyl isocyanates generated by the reaction of primary amides with oxalyl chloride to give symmetrical and unsymmetrical diacyl urea derivatives, acyl ureas/carbamates/thiocarbamates, and related compounds. This method provides means for convenient one-pot, two-step synthesis of compounds bearing urea, carbamate, and other functional groups from cheap and commercially available starting reagents. It is expected that the results presented in this report will expand the medicinal chemist’s toolbox.

Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia

A series of 6-acylureido derivatives containing a 3-(pyrrol-2- ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2- one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2- fluoro-4-methoxybenzoyl)ureido)-2-oxoindolin-3-ylidene)methyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML.

INDOLIN-2-ONE DERIVATIVES AS PROTEIN KINASE INHIBITORS

A novel class of indoline-2-one derivatives are disclosed. These compounds are protein kinase inhibitors which are useful for treating hyperproliferative diseases such as cancer.

N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods

N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl) ureas (substituents: Me, Ph, Cl, OH, OMe, NO2, NH2, COOH, and COOMe) were synthesised by ZnCl2 catalysed acylation of O-peracetylated β-d-glucopyranosyl urea as well as in reactions of O-peracetylated or O-unprotected glucopyranosylamines and acyl-isocyanates. O-deprotections were carried out by base or acid catalysed transesterifications where necessary. Kinetic studies revealed that most of these compounds were low micromolar inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb). The best inhibitor was the 4-methylbenzoyl compound (Ki = 2.3 μM). Crystallographic analyses of complexes of several of the compounds with RMGPb showed that the analogues exploited, together with water molecules, the available space at the β-pocket subsite and induced a more extended shift of the 280s loop compared to RMGPb in complex with the unsubstituted benzoyl urea. The results suggest the key role of the water molecules in ligand binding and structure-based ligand design. Molecular docking study of selected inhibitors was done to show the ability of the binding affinity prediction. The binding affinity of the highest scored docked poses was calculated and correlated with experimentally measured Ki values. Results show that correlation is high with the R-squared (R2) coefficient over 0.9.

COMPOSITIONS AND METHODS FOR MODULATING C-KIT AND PDGFR RECEPTORS

The invention provides compounds and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, as well as methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of c-kit, PDGFR , PDGFR , CSF1R, Abl, BCR-Abl, CSK, JNK1, JNK2, p38, p70S6K, TGF , SRC, EGFR, trkB, FGFR3, FLT3, Fes, Lck, Syk, RAF, MKK4, MKK6, SAPK2 , BRK, KDR, c-raf or b-raf kinase, or mutant forms thereof.