1246533-06-1

Upstream product

• 1233145-65-7 4-(3-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 
• 59557-91-4 4-bromo-2-methoxyaniline 
• 375853-82-0 tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate 

Downstream Products

• 1089280-53-4 tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate 
• 1390657-97-2 tert-butyl 4-(4-((2-chloro-5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-4-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate 
• 1390657-98-3 tert-butyl 4-(4-((2-(2,6-dichlorobenzyl)-5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-4-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate 
• 1390657-99-4 tert-butyl 4-(3-methoxy-4-(5-oxo-2-vinyl-5,6-dihydropyrido[3,2-d]pyridazin-4-ylamino)phenyl)piperidine-1-carboxylate 
• 1390658-00-0 tert-butyl 4-(3-methoxy-4-(2-(2-morpholinoethyl)-5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-4-ylamino)phenyl)piperidine-1-carboxylate 
• 1390658-02-2 (E)-tert-butyl 4-(4-(2-(2-cyclopropylvinyl)-5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-4-ylamino)-3-methoxyphenyl)piperidine-1-carboxylate 
• 1390658-03-3 tert-butyl 4-(4-(2-(2-cyclopropylethyl)-5-oxo-5,6-dihydropyrido[3,2-d]pyridazin-4-ylamino)-3-methoxyphenyl)piperidine-1-carboxylate 
• 1390658-08-8 tert-butyl 4-(4-((2-(2-fluorobenzyl)-5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-4-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate 
• 1390656-28-6 2-(2-fluorobenzyl)-4-{[2-methoxy-4-(piperidin-4-yl)phenyl]amino}pyrido[2,3-d]pyridazin-5(6H)-one 
• 1390658-91-9 tert-butyl 4-(4-((2-(2,5-difluorobenzyl)-5-oxo-5,6-dihydropyrido[2,3-d]pyridazin-4-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate 
• 1124330-14-8 2-methoxy-4-(1-methylpiperidin-4-yl)aniline 

Relevant academic research and scientific papers

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

BICYCLIC INHIBITORS OF ALK

The present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, wherein R1, X, Y, Z, A, B, G1, and n are defined in the description. The present invention relates also to compositions containing said compounds which are useful for inhibiting kinases such as ALK and methods of treating diseases such as cancer.

BICYCLIC CARBOXAMIDE INHIBITORS OF KINASES

Compounds of formula (I) or pharmaceutical acceptable salts are provided, wherein X1~X5, R1~R3, A, B, Z and n are defined in the description. And compositions containing said compounds, and the uses for inhibitors of kinases such as ALK, and the uses for treating cancer thereof are provided.

COMPOUNDS AND THERAPEUTIC USES THEREOF

The invention relates to compounds, pharmaceutical compositions, and uses thereof, including therapeutic uses thereof, such as methods useful for treating cancer.