50424-88-9

Upstream product

• 385-02-4 6-fluoro-2-nitrobenzoic acid 
• 769-10-8 1-fluoro-2-methyl-3-nitrobenzene 

Downstream Products

• 148857-97-0 2-fluoro-6-nitrobenzamide 
• 870281-83-7 2-fluoro-6-nitro-N-phenyl-benzamide 
• 870281-84-8 (S)-[1-(2-fluoro-6-nitro-benzoy)phenylaminocarbonyl]propyl carbamic acid tert-butyl ester 
• 120275-71-0 N-benzyl-2-fluoro-6-nitrobenzamide 
• 1365993-00-5 2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-fluorobenzonitrile 
• 1365992-99-9 3-fluoro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile 
• 1365992-98-8 3-fluoro-2-(7-fluoro-5-oxythiazolo[5,4-c]pyridin-2-yl)-benzonitrile 

Relevant academic research and scientific papers

Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation

Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC50 = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI50 value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kβ. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.

Selective PI3Kdelta inhibitor and application thereof

The present application relates to a compound as a selective PI3Kdelta kinase inhibitor comprising a compound of the following formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid,metabolite or prodrug thereof, wherein X, R1, R2, R3, R4, R5 and R6 are as defined in the specification. The present application also relates to methods and uses of using such kinase inhibitor to inhibit PI3Kdelta kinase activity or to treat or prevent diseases or disorders associated with tyrosine kinase activity of PI3Kdelta.

Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3 H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3KδInhibitor for the Treatment of Chronic Obstructive Pulmonary Disease

Accumulated pieces of evidence have shown that PI3Kδplays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδinhibitor (S)-18. In the biochemical assay, (S)-18 inhibits PI3Kδ(IC50 = 14 nM) with high selectivity over other class I PI3Ks (56～83 fold). (S)-18 also achieves good selectivity over other protein kinases in the kinome (S-score (35) = 0.015). In the cell, (S)-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, (S)-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC50 > 10 μM). In vivo, (S)-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that (S)-18 might be a new potential therapeutic candidate for COPD.

Conformationally restricted quinazolone derivatives as PI3Kδ-selective inhibitors: the design, synthesis and biological evaluation

A series of structurally novel quinazolone-based PI3Kδ-selective inhibitors were designed and synthesized via the approach of conformational restriction. The majority of them exhibited two-digit to single-digit nanomolar IC50 values against PI3Kδ, along with low micromolar to submicromolar GI50 values against human malignant B-cell line SU-DHL-6. The representative compound, with the most potent PI3Kδ inhibitory activity (IC50 = 6.3 nM) and anti-proliferative activity (GI50 = 0.21 μM) in this series, was further evaluated for its PI3Kδ selectivity, capability to down-regulate PI3K signaling in SU-DHL-6 cells, in vitro metabolic stability, and pharmacokinetic (PK) properties. The experimental results illustrated that this compound, as a promising lead, merits extensive structural optimization for exploring novel PI3Kδ-selective inhibitors as clinical candidates.

AUTOMATED RADIOSYNTHESIS

The present invention provides a method to obtain radiofluorinated compounds useful for in vivo imaging GABAA receptors. The method of the invention is high-yielding and may conveniently be carried out on an automated synthesizer such as FastlabTM. A further aspect of the invention is a cassette suitable for carrying out the automated method of synthesis of the invention. Novel precursor compounds useful in the method of the invention are also provided, as are a number of novel compounds obtained by the method of the invention.

A novel highly stereoselective synthesis of 2,3-disubstituted 3H-quinazoline-4-one derivatives

Figure presented An efficient three-step synthesis of chiral 3H-quinazoline-4-one derivatives from commercial materials is disclosed. The Mumm reaction of imidoyl chloride with α-amino acids followed by reductive cyclization affords enantiomerically pure (ee >93%) quinazoline-4-ones in good overall yield. A comparison with existing approaches indicates that this method is superior for hindered substrates.

METHOD OF PREPARING 3-PHENYL-2-[9H-PURIN-6-YLAMINO)-METHYL]-3H-QUINAZOLIN-4-ONE AND SUBSTITUTED AND RELATED COMPOUNDS

A method of synthesizing compounds of structural formulae (II), (IIa), and (III), in high yield and high stereospecific selectivity is disclosed. (IIa, R5≠H, S-enantiomer)

Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors

Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.

Antagonist, Partial Agonist, and Full Agonist Imidazoquinoxaline Amides and Carbamates Acting through the GABAA/benzodiazepine Receptor

(4RS)-1-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydroimidazopyrroloquinoxalin-10(11H)-one (1a), 5-benzoyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazoquinoxaline (13b), and tert-butyl (4S)-12,12a-dihydroimidazopyrroloquinoxaline-1-carboxylate (1e), as well as other imidazoquinoxaline amides and carbamates, represent a new series of compounds which bind with high affinity to the GABAA/benzodiazepine receptor.These compound exhibit a wide range of intrinsic efficacies as measured by TBPS binding ratios.The synthesis of 1a begins with the addition of DL-glutamic acid to 1-fluoro-2-nitrobenzene, followed by reduction of the nitro group and subsequent ring closure to form 3-(carbethoxymethyl)-1,2,3,4-tetrahydroquinoxalin-2-one, followed by a second ring closure to afford (4RS)-1,5-dioxo-1,2,3,4,5,6-hexahydropyrroloquinoxaline as the key intermediate.Appendage of a substituted imidazo ring via the anion of 5-cyclopropyl-1,2,4-oxadiazol-3-yl gives 1a.The (-) and (+)-isomers of 1a were prepared from 1-fluoro-2-nitrobenzene and L- and D-glutamic acid, respectively. 1a and its enantiomers demonstrated affinity for flunitrazepam binding site with Ki's of 0.87, 0.62, and 0.65 nM, respectively.