77324-87-9

Usage

Chemical Properties

White crystalline powder

InChI:InChI=1/C9H9NO4/c1-6-3-4-7(10(12)13)5-8(6)9(11)14-2/h3-5H,1-2H3

Upstream product

• 89-71-4 2-Methyl-benzoic acid methyl ester 
• 67-56-1 methanol 
• 1975-52-6 5-nitro-o-toluic acid 
• 7697-37-2 nitric acid 
• 939-83-3 2-cyano-4-nitrotoluene 
• 118-90-1 ortho-methylbenzoic acid 
• 7745-93-9 2-bromo-4-nitrotoluene 
• 64688-68-2 2-methyl-5-nitrobenzoyl chloride 
• 201230-82-2 carbon monoxide 
• 7745-92-8 2-iodo-1-methyl-4-nitrobenzene 
• 74-88-4 methyl iodide 
• 186581-53-3 diazomethane 
• 50825-99-5 2-methyl-5-nitrobenzamide 

Downstream Products

• 63134-59-8 4-nitro-trans-stilbene-carboxylic acid-⁽²⁾ 
• 52090-24-1 methyl 2-methyl-3,5-dinitrobenzoate 
• 18595-12-5 methyl 5-amino-2-methylbenzoate 
• 101714-14-1 4-nitro-phthalic acid-2-methyl ester 
• 90725-68-1 methyl 2-(bromomethyl)-5-nitrobenzoate 
• 1036388-63-2 (E)-methyl 2-(2-(dimethylamino)vinyl)-5-nitrobenzoate 
• 1184301-81-2 2-methoxymethyl-5-nitrobenzoic acid 
• 1184301-84-5 methyl 5-(((tert-butoxycarbonyl)amino)methyl)-2-methylbenzoate 
• 1184301-85-6 5-(N-tert-butoxycarbonylmethyl)methylamino-2-methylbenzoic acid methyl ester 
• 165950-06-1 5-(((tert-butoxycarbonyl)amino)methyl)-2-methylbenzoic acid 
• 1574531-88-6 2-[(bis-pyridin-2-ylmethylamino)methyl]-5-nitrobenzoic acid methyl ester 
• 1574531-89-7 2-[(bis-pyridin-2-ylmethylamino)methyl]-5-nitrobenzoic acid 
• 1036388-65-4 2-(2,4-dimethoxybenzyl)-7-nitroisoquinolin-1(2H)-one 
• 564467-91-0 2-methyl-6-nitroisoindolin-1-one 

Relevant academic research and scientific papers

Copper-promoted direct amidation of isoindolinone scaffolds by sodium persulfate

Isoindolinones are ubiquitous structural motifs in natural products and pharmaceuticals. Establishing an efficient method for structural modification of isoindolinones could significantly facilitate new drug development. Herein, we describe copper-promoted direct amidation of isoindolinone scaffolds mediated by sodium persulfate. The method exhibits mild reaction conditions and high site-selectivity, and enables the structural modification of the drug indobufen ester with various amides with yields of 49 to 98%. It is also gram-scalable. Additionally, the reaction mechanism appears to involve a radical and a carbocationic pathway.

PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH

The invention relates to MKK4 (mitogen-activated protein kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The MKK4 inhibitors selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7.

HETEROARYL COMPOUNDS AND USES THEREOF

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of one or more protein kinases. Such compounds have general formula I or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, W, Ry, R3 and R4 are as defined herein.

Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors

Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

Design, synthesis and biological evaluation of isoquinoline-based derivatives as novel histone deacetylase inhibitors

The design, synthesis and biological evaluation of a series of isoquinoline-based hydroxamic acid compounds as novel HDACs inhibitors were reported herein. A detailed SAR study showed most of the compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10c against HDAC1, 3, 6 were 4.17 ± 0.11 nM, 4.00 ± 0.10 nM, 3.77 ± 0.07 nM, respectively. Most of the compounds showed great anti-proliferative activities against RPMI 8226, HCT 116 and Hep G2 cells. The IC50 values of compounds 10a-h against RPMI 8226 cancer cell proliferation were all below 1 μM. HCT 116 cell was sensitive to the compounds 10a, 10f-g and 18a with the IC50 values 0.3 μM. The active compounds 10a-d did not show inhibitory activity against hERG channel. All these evidence indicated these compounds had great potential as HDACs inhibitors for the further development.

SUBSTITUTED BICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS

The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.

Series of structural and functional models for the ES (enzyme-substrate) complex of the Co(II)-containing quercetin 2,3-dioxygenase

A series of mononuclear CoII-flavonolate complexes [Co IILR(fla)] (LRH = 2-{[bis(pyridin-2-ylmethyl) amino]methyl}-p/m-R-benzoic acid; R = p-OMe (1), p-Me (2), m-Br (4), and m-NO2 (5); fla = flavonolate) were designed and synthesized as structural and functional models for the ES (enzyme-substrate) complexes to mimic the active site of the Co(II)-containing quercetin 2,3-dioxygenase (Co-2,3-QD). The metal center Co(II) ion in each complex shows a similar distorted octahedral geometry. The model complexes display high enzyme-type dioxygenation reactivity (oxidative O-heterocyclic ring opening of the coordinated substrate flavonolate) at low temperature, presumably due to the attached carboxylate group in the ligands. The reactivity exhibits a substituent group dependent order of -OMe (1) > -Me (2) > -H (3)14b > -Br (4) > -NO2 (5), and the Hammett plot is linear (ρ = -0.78). This can be explained as the electronic nature of the substituent group in the ligands may influence the conformation and redox potential of the bound flavonolate and finally bring different reactivity. The structures, properties, and reactivity of the model complexes show some dependence on the substituent group in the supporting model ligands, and there is some relationship among them. This study is the first example of a series of structural and functional ES models of Co-2,3-QD, with focus on the effects of the electronic nature of substituted groups and the carboxylate group of the ligands to the dioxygenation reactivity, that will provide important insights into the structure-property-reactivity relationship and the catalytic role of Co-2,3-QD.

Metabolically stable dibenzo[ b, e ]oxepin-11(6 H)-ones as highly selective p38 MAP kinase inhibitors: Optimizing anti-cytokine activity in human whole blood

Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H) -ones were synthesized and tested in a p38α enzyme assay for their inhibition of tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown that the additional introduction of hydrophilic residues at position 9 leads to a substantial improvement of the inhibitory potency and metabolic stability. Using protein X-ray crystallography, the binding mode of the disubstituted dibenzoxepinones and the induction of a glyince flip in the hinge region were confirmed. The most potent compound of this series, 32e, shows an outstanding biological activity on isolated p38α, with an IC50 value of 1.6 nM, extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and low ATP competitiveness. The ability to inhibit the release of TNF-α from human whole blood was optimized down to an IC50 value of 125 nM. With the promising dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.

COMPOUNDS AND METHODS FOR TREATING RESPIRATORY DISEASES

Described herein are compounds and compositions, and methods for using the compounds and compositions, for treating respiratory diseases and illness, such as severe acute respiratory syndrome (SARS).

Discovery and SAR of 5-(3-Chlorophenylamino)benzo[ c ][2,6]naphthyridine-8- carboxylic Acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the Treatment of Cancer

Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2s small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (Ki = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.