691872-15-8

Usage

Uses

Used in Pharmaceutical Industry:
5-Bromo-2-nitro-3-pyridinol is used as a key intermediate in the synthesis of novel antitumor agents for the treatment of cancers with ALK mutations. Its application is particularly relevant in overcoming resistance to Crizotinib, a widely used ALK inhibitor, by providing a structural foundation for the development of more effective and selective inhibitors.
Used in Cancer Research:
In the field of cancer research, 5-Bromo-2-nitro-3-pyridinol serves as a valuable tool for designing and testing new compounds that can effectively target and inhibit ALK mutations. This contributes to the advancement of cancer therapies and the improvement of patient outcomes, especially for those with cancers that have developed resistance to standard treatments.
Used in Drug Development:
5-Bromo-2-nitro-3-pyridinol is utilized in drug development as a starting point for creating new pharmaceuticals that can address the unmet need for effective treatments against cancers with ALK mutations. Its role in this process is crucial, as it provides a chemical basis for the design of innovative and more potent ALK inhibitors that can overcome resistance mechanisms.

Upstream product

• 74115-13-2 5-bromopyridine-3-ol 

Downstream Products

• 756503-69-2 (±)-5-bromo-3-(1-(2,6-dichloro-3-fluoropheny)ethoxy)pyridin-2-amine 
• 1394346-24-7 (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine 
• 1558007-81-0 (R)-3-[1-(2,5-difluorophenyl)ethoxy]-5-(3-methyl-1H-pyrazol-4-yl)pyridin-2-amine 
• 1346815-25-5 2-[(1R)-1-{[2-amino-5-(3-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]oxy}ethyl]-4-fluorobenzonitrile 
• 1558007-82-1 3-[(1R)-1-(5-fluoro-2-methoxyphenyl)ethoxy]-5-(5-methyl-1H-pyrazol-4-yl)pyridin-2-amine 
• 1346818-23-2 5-bromo-3-[(R)-1-(5-fluoro-2-methoxyphenyl)ethoxy]pyridin-2-ylamine 
• 1346818-20-9 (R)-5-bromo-3-[1-(2,5-difluorophenyl)ethoxy]pyridin-2-amine 
• 1346818-07-2 (R)-5-bromo-3-[1-(2,5-difluorophenyl)ethoxy]-2-nitropyridine 
• 1428476-86-1 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester 
• 877399-52-5 crizotinib 
• 1394346-15-6 (R)-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)-ethoxy)pyridin-3-yl)-3-fluorophenyl)dimethylphosphine oxide 

Relevant academic research and scientific papers

Macrocyclic JAK2 inhibitor and application thereof

The invention relates to a macrocyclic JAK2 inhibitor and an application thereof. Specifically, the invention relates to a compound shown as a formula I and an application of the compound in treatingJAK2-mediated related diseases and preparing medicines for treating the JAK2-mediated related diseases.

SELECTIVE JAK2 INHIBITOR AND APPLICATION THEREOF

Provided is a selective JAK2 inhibitor and application thereof. In particular, it relates to the compound of the following Formula (I), and the use of the compound in the treatment of JAK2-mediated related diseases and in the preparation of the medicament for treating JAK2-mediated related diseases.

Discovery and optimization of 2-aminopyridine derivatives as novel and selective JAK2 inhibitors

Janus kinases (JAKs) including JAK1, JAK2, JAK3, and TYK2 are members of a family of intracellular nonreceptor tyrosine kinases, which have been demonstrated to be critical in the cell signaling pathway and involved in inflammatory diseases and cancer. V617F mutation in JAK2 has been implicated in polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis (MF). Here, we described the design, synthesis, and biological evaluation of a series of 2-aminopyridine derivatives. The results of enzymatic activity assays supported compound 16m-(R) as a potential and selective JAK2 inhibitor, which exhibited high inhibitory activity with an IC50 of 3 nM against JAK2, and 85- and 76-fold selectivity over JAK1 and JAK3, respectively. Structure-activity relationships (SAR) and mechanistic analysis demonstrated that 16m-(R) might be a promising selective JAK2 inhibitor for further study.

HPK1 INHIBITORS, PREPARATION METHOD AND APPLICATION THEREOF

Disclosed are HPK-1 inhibitors having a structure represented by Formula (X), pharmaceutical compositions comprising the HPK-1 inhibitors, methods of using the HPK-1 inhibitors, such as treating cancers, methods of preparing the HPK-1 inhibitors, and the synthetic intermediates.

Design and Synthesis of a Series of Novel Macrocycle Janus Kinase 2 Inhibitors

Macrocycle has attracted the attention of many researchers in the field of medicinal chemistry due to its unique advantages and good prospects, but the difficulties in drug design and synthesis of macrocycle limit its applications. In this study, a series of macrocyclic derivatives designed from anaplastic lymphoma kinase (ALK) inhibitor lorlatinib were synthesized as Janus kinase 2 (JAK2) selective inhibitors. Among them, 17f had the best inhibitory activity (IC50 = 0.177 μmol·L–1) and selectivity for JAK2 over JAK1 and JAK3, which indicated that design of the macrocyclic derivatives might be a feasible strategy for the discovery of novel selective JAK2 inhibitors.

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.

Development of a modified process for the kilogram-scale synthesis of c-Met/ALK inhibitor HS-10168

A modified synthetic route to c-Met/ALK inhibitor HS-10168 has been developed on a kilogram scale. The key steps of the new process include a Suzuki coupling reaction of nitro-containing bromopyridine 6 and para-phenol boronate 9 to give intermediate 10, which was then converted to its triflate 11. The phosphorus group was introduced by coupling of 11 and dimethylphoshine oxide 8 to give compound 12, which was reduced to produce HS-10168.

Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6)

Abstract Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile.

PHOSPHORUS CONTAINING COMPOUNDS AS PROTEIN KINASE INHIBITORS

The present invention relates to compounds represented by formula (I), which can modulate the activity of protein kinases. The invention also relates to a composition containing a compound of formula (I), and a method for synthesizing and using such compound for preventing or treating ALK or cMet mediated disorders or conditions.