650628-54-9

Upstream product

• 650628-53-8 1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one 
• 3471-32-7 4-Methoxyphenylhydrazine 
• 5305-40-8 2,6-dichloro-pyrimidine carbaldehyde 
• 1235035-27-4 1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(3aH)-one 
• 104-94-9 4-methoxy-aniline 
• 1429924-36-6 4,6-dichloro-5-((2-(4-methoxyphenyl)hydrazono)methyl)pyrimidine 
• 19501-58-7 4-methoxyphenylhydrazine hydrochloride 
• 15001-13-5 ethyl 5-amino-1-(4-methoxy)phenyl-1H-pyrazole-4-carboxylate 

Downstream Products

• 650628-52-7 4-hydrazino-1-[4-methoxyphenyl]-1H-rzl[3,4-d]pyrimidine 
• 1235035-29-6 4-(4-isopropylamino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol 
• 393845-13-1 4-[1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]morpholine 
• 1235035-96-7 4-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol 
• 1235035-61-6 4-(4-(3-(dimethylamino)propylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol 
• 393845-22-2 C₁₈H₂₁N₅O 

Relevant academic research and scientific papers

Identification of novel GLUT inhibitors

The compound class of 1H-pyrazolo[3,4-d]pyrimidines was identified using HTS as very potent inhibitors of facilitated glucose transporter 1 (GLUT1). Extensive structure–activity relationship studies (SAR) of each ring system of the molecular framework was established revealing essential structural motives (i.e., ortho-methoxy substituted benzene, piperazine and pyrimidine). The selectivity against GLUT2 was excellent and initial in vitro and in vivo pharmacokinetic (PK) studies are encouraging.

Discovery of a potent and selective BCL-XLinhibitor with in vivo activity

A-1155463, a highly potent and selective BCL-XLinhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XLbiology as well as a productive lead structure for further optimization.

Synthesis of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines from 4,6-dichloropyrimidine-5-carboxaldehyde: Insights into selectivity and reactivity

Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5- carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity trends are rationalized through consideration of the proposed reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines. Georg Thieme Verlag Stuttgart. New York.

Selective synthesis of 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines

Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5- carboxaldehyde with various hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective and high-yielding manner are presented. For aromatic hydrazines, the reaction is performed in the absence of an external base, which promotes exclusive hydrazone formation. The hydrazones subsequently cyclize at an elevated temperature to form the desired pyrazolo[3,4-d]pyrimidine products. For aliphatic hydrazines, the reaction sequence proceeds as a single step in the presence of an external base.

N-N bond-forming cyclization for the one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines

An efficient one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines in good yield and under mild reaction conditions is described. By exploiting electron-deficient hydroxylamines, the substituted oxime products were formed with very high E-diastereoselectivity. The key step utilizes a cyclization reaction upon an oxime derived from hydroxylamine-O-sulfonic acid to form the N-N bond of the product.

HETEROCYCLIC COMPOUNDS AND METHODS OF USE

In one aspect, the present invention provides for a compound of Formula I; in which the variable X1a, X1b, X1c, X1d, Q, A, R1, B, L, E, and the subscripts m and n have the meanings as described herein. In another aspect, the present invention provides for pharmaceutical compositions comprising compounds of Formula I as well as methods for using compounds of Formula I for the treatment of diseases and conditions (e.g., cancer, thrombocythemia, etc) characterized by the expression or over-expression of Bcl-2 anti-apoptotic proteins, e.g., of anti-apoptotic Bcl-xL proteins.

A one step synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines

A new synthesis of 1-alkylpyrazolo[5,4-d]pyrimidines is described. The reaction of 4,6-dichloropyrimidine-5-carbaldehyde with various substituted hydrazines provides such compounds in a single step from commercially available starting materials. This method has advantages over methods currently described in the literature for the construction of such ring systems.

Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors

A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar1) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range.