956388-06-0

Upstream product

• 87-60-5 3-chloro-2-methylbenzenamine 
• 110-87-2 3,4-dihydro-2H-pyran 
• 13096-96-3 4-chloro-1H-indazole 

Downstream Products

• 956388-05-9 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 
• 1146955-35-2 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 

Relevant academic research and scientific papers

Application of C-H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib

This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed C-H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.

Selectively Targeting the Kinome-Conserved Lysine of PI3Kδ as a General Approach to Covalent Kinase Inhibition

Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to 200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

CHEMICAL COMPOUNDS

The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular PI3-kinase activity.

PROCESSES TO MAKE INDAZOLE DERIVATIVES

The present invention provides novel processes for preparing compounds of formula (IV) and salts thereof, novel intermediates,and a novel salt and polymorph thereof.

DIOXINO-AND OXAZIN-[2,3-D]PYRIMIDINE PI3K INHIBITOR COMPOUNDS AND METHODS OF USE

Dioxino-and oxazin-[2,3-d]pyrimidine PI3K inhibitor compounds of Formula I with anti-cancer activity, anti-in-flammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are de-scribed. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.

A practical synthesis of a PI3K inhibitor under noncryogenic conditions via functionalization of a lithium triarylmagnesiate intermediate

We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling. Metalation of the thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under noncryogenic conditions to produce the corresponding aldehyde. We also investigated aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and Suzuki-Miyaura cross-coupling. Final deprotection and salt formation afforded the API.

METHOD FOR MANUFACTURING A BORONIC ACID ESTER COMPOUND

The present invention relates to a method for manufacturing a boronic acid ester compound, characterized by reacting an aryl halide compound and a diboron ester compound in the presence of a nitrogen-containing organic base, a nickel catalyst, a phosphine compound and a solvent. According to the manufacturing method of the present invention, even if a nickel catalyst is used as the catalyst, a desired boronic acid ester compound can be obtained in a sufficiently high yield. Furthermore, even if aryl chloride or aryl bromide having relatively low price and low reactivity, was used as the aryl halide compound, a desired boronic acid ester compound can be obtained in a sufficiently high yield.

TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS OF USE

Tricyclic PI3k inhibitor compounds of Formula I with anti-cancer activity, anti- inflammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are described. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions. Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.

Pyridinium p-toluenesulfonate: A mild and efficient catalyst for the regioselective tetrahydropyranylation of indazole derivatives under solvent-free conditions

An efficient and regioselective tetrahydropyranyl (THP) protection on substituted 1H-indazoles in solution phase as well as under solvent-free conditions catalyzed by microwave irradiation in the presence of pyridinium p-toluenesulfonate (PPTS) as mild catalyst.

METHOD FOR MANUFACTURING A BORONIC ACID ESTER COMPOUND

The present invention relates to a method for manufacturing a boronic acid ester compound, characterized by reacting an aryl halide compound and a diboron ester compound in the presence of a nitrogen-containing organic base, a nickel catalyst, a phosphine compound and a solvent. According to the manufacturing method of the present invention, even if a nickel catalyst is used as the catalyst, a desired boronic acid ester compound can be obtained in a sufficiently high yield. Furthermore, even if aryl chloride or aryl bromide having relatively low price and low reactivity, was used as the aryl halide compound, a desired boronic acid ester compound can be obtained in a sufficiently high yield.